REGULATION OF MANDIBULAR GROWTrH AND MORPHOGENESIS

Mina Mina Department of Pediatric Dentistry, School of Dental Medicine, University of Connecticut Health (enter, Farmington, al 06030; Mina@nsoL.uchc.edu
ABSTRACT: The development of the vertebrate face is a dynamic process that starts with the formation of facial processes/prominences. Facial processes are small buds made up of mesenchymal masses enclosed by an epithelial layer that surround the primitive mouth. The 2 maxillary processes, the 2 lateral nasal processes, and the frontonasal processes form the upper jaw. The lower jaw is formed by the 2 mandibular processes. Although the question of the embryonic origin of facial structures has received considerable attention, the mechanisms that control differential growth of the facial processes and patterning of skeletal tissues within these structures have been difficult to study and still are not well-understood. This has been partially due to the lack of readily identifiable morphologically discrete regions in the developing face that regulate patterning of the face. Nonetheless, in recent years there has been significant progress in the understanding of the signaling network controlling the patterning and development of the face (for review, see Richman et al., 1991; Francis-West et al., 1998). This review focuses on current understanding of the processes and signaling molecules that are involved in the formation of the mandibular arch.
Key words. Mandibular processes, branchial arches, signaling molecules, epithelial-mesenchymal interactions, transcription factors, secreted factors, chick, mouse, growth, patterning, morphogenesis.

Introduction
During normal development, the lower jaw is formed from the mandibular component of the first branchial arch. The mandibular processes are bilaterally symmetrical structures located below the future mouth cavity and composed of mesenchymal tissue enclosed by an epithelial layer of ectodermal and endodermal origin. After their initial formation, these processes undergo considerable outgrowth along all 3 axes, merge in the midline region, and give rise to the elongated triangular-shaped lower jaw. In addition to merging in the midline region, mandibular processes also fuse/merge at the lateral corners with the maxillary process and at their lower borders with the hyoid process. The mesenchyme of the mandibular processes, as in other facial processes, is derived from cranial neural crest cells (CNCC) and paraxial mesoderm. CNCC give rise to the majority of the craniofacial skeleton (for reviews, see Le Douarin et al., 1994; Osumi-Yamashita et al., 1997; Schilling, 1997). On the other hand, the paraxial mesoderm forms the craniofacial muscles along with some skeletal elements in the skull and vascular tissues (Noden, 1983b, 1988; Couly et al., 1992, 1993). The skeletogenic potential of neural crest cells (NCC) is restricted to the cephalic
region down to the level of somite 5. In addition to giving rise to skeletal structures, CNCC give rise to the peripheral nervous system and connective tissues associated with the facial muscles (Noden, 1986, 1988; Couly et al., 1992; Kontges and Lumsden, 1996; Osumi-Yamashita et al., 1997). The fate and final derivatives of CNCC cells have been extensively analyzed in avian and mammalian embryos (for reviews, see Le Douarin et al., 1994,1997; Osumi-Yamashita et al., 1997; Teillet et al., 1999). In addition, after the identification of rhombomeres (R), a series of segmented structures in the hindbrain, an elegant scheme of the migratory routes and derivatives of CNCC has been generated through short-term and long-term

et al.,

The results of these studies indicate that, in contrast to the NCC of the rest of the body, the hindbrain CNCC migrate in 3 non-mixing separate streams from RI and R2, from R4 and from R6 (Lumsden et al., 1991; Osumi-Yamashita et al., 1997). The formation of 3 separated streams of migrating cells is due to lack of emigration and migration of CNCC from R3 and R5 (Lumsden et al., 1991; Couly et al., 1996). The lack of emigration of CNCC from R3 and R5 is mainly due to apoptotic elimination of NCC and is regulated by molecules such as BMP-4 and Msx2 and by interactions with neighboring rhombomeres (Graham et al., 1996; Maden et al., 1997; Takahashi et al., 1998). More recent studies indicate that crest depletion from R3 and R5 is not absolute and that a small number of NCC from R3 and R5 survive the apoptotic elimination and join migratory cells in adjacent rhombomeres (Sechrist et al., 1993; Birgbauer et al., 1995; Kontges and Lumsden, 1996). Short-survival fate-mapping of CNCC in chick embryos showed that CNCC originating from R4 and R6 populate the second and third branchial arches, respectively (Lumsden et al., 1991; Couly et al., 1996, 1998). A mixed population of CNCC from the posterior mesencephalon, Rl, and R2 (Lumsden et al., 1991) colonizes the first branchial arch (maxillary and mandibular processes). Long-survival fate-mapping with use of the quail marker extended these observations and showed the compound nature of the mandibular skeleton in which CNCC originating from multiple rhombomeres (Rl, R2, and R4) participate in the formation of the mandibular arch skeleton (Couly et al., 1996; Kontges and Lumsden, 1996). Interestingly, the mandibular arch skeleton displays an organization that precisely reflects the rostrocaudal order of crest emigration. The proximal elements (the major part of Meckel's cartilage, and dentary and splenial bones) are derived from the midbrain crest. The caudal
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fate-mapping (Lumsden et al., 1991; Serbedzija et al., 1992; Couly 1993, 1996, 1998; Kontges and Lumsden, 1996).

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skeletal structures of the mandibular arch (elements around the lower jaw joints and close to the middle ear structures, such as the articular and its internal process, angular, suprangular, and quadrate) are formed mainly by NCC from Rl and R2. Kontges and Lumsden (1996) showed that the most caudal element of the lower jaw in chick embryos, the retroarticular process of the Meckel's cartilage, is derived from CNCC originating from R4 and a small number of NCC from R3 and R5 that survive apoptosis. On the other hand, Couly et al. (1996) found no contribution of R4 to the caudal skeletal elements. More recent labeling studies in chick (Sohal et al., 1999) and mouse (Chai et al., 2000) embryos showed that, in addition to the CNCC, Meckel's cartilage is populated by non-CNCC. Studies in chick embryos showed that cells emigrating from the ventral region of the neural tube (VENT) also make a significant contribution to Meckel's cartilage (Sohal et al., 1999). In addition, Kontges and Lumsden (1996) showed that the same groups of CNCC also give rise to the connective tissue of individual mandibular muscles and their respective attachment sites to the skeletal elements in the mandibular arch and the cranial base. While the CNCC from the posterior mesencephalon and RI and R2 mix together, there is no mixing between this population and those originating from R4 that give rise to the retroarticular process and connective tissue of the hyoid arch muscle (Kontges and Lumsden, 1996). Cell transplantation and DiI labeling experiments also showed similarities between the axial level of origin for the paraxial mesoderm and the CNCC populating each branchial arch (Noden, 1983b, 1986, 1988; Trainor et al., 1994; Trainor and Tam, 1995; Hacker and Guthrie, 1998). These studies in mouse and chick embryos showed that cranial paraxial mesoderm migrates in overlapping streams into the nearest branchial arch. Mesoderm originating from somitomeres III and IV enters the developing mandibular and hyoid arch and colonizes their core, a region known to correspond to the muscle mass where they express myogenic markers such as Myf5, MyoD, and myogenin (Trainor and Tam, 1995; Hacker and Guthrie, 1998). In contrast to the regions occupied by paraxial mesenchyme, the migrating CNCC colonize the periphery of each branchial arch (Lumsden et al., 1991; Trainor and Tam, 1995; Hacker and Guthrie, 1998). In the branchial arches, unlike other regions in the face, there is a distinct segregation of these 2 cell populations (Trainor and Tam, 1995). For many years, it has been thought that patterning of the skeletal elements in the mandibular arch is the result of intrinsic morphogenetic specification in CNCC. This possibility was suggested by the results of a series of hetero- and isotopic grafting experiments in amphibian and avian embryos (Horstadius and Sellman, 1946; Wagner, 1949; Noden, 1983a, 1988). The quail-chick transplantation experiments demonstrated that when presumptive first-arch CNCC (anterior region of the hindbrain Rl and R2 and mesencephalic CNCC) are transplanted into the presumptive second-arch region (R4/R6), the grafted CNCC migrate ventrally to the second arch but subsequently give rise to a subset of first-arch-specific structures and form a partially duplicated mandibular arch skeleton (Noden, 1983a; Couly et al., 1998). One of the main conclusions drawn from these experiments is that, in contrast to trunk NCC, CNCC are morphogenetically pre-specified, and the patterns of the CNCC-derived skeleton are imprinted in the pre-migratory CNCC while they are still within the neural tube. However, the concept of morphogenetic specification of cra2001) 12(4) 276-300 (2001) 12(4):276-300

nial NCC has remained controversial for many years, because no other subpopulation of pre-migratory NCC other than those giving rise to the mandibular arch showed such pre-specification in the patterns of their derivatives. In addition, it was shown that transplantation of mesencephalic NCC (which normally give rise to skeletal elements in the frontonasal mass and maxillary and peri-ocular region) into the presumptive second- and thirdarch NCC also gave rise to a duplicated subset of first-arch-specific structures (Noden, 1983a). Furthermore, these observations are in contrast to the outcome of transplantation of the presumptive first-arch NCC into the rostral or more caudal regions which gave rise to normal head skeletal structures and did not form mandibular arch structures (Noden, 1978, 1986). The first family of genes suggested to be involved in prespecification of CNCC and branchial arch development was the Hox genes (for reviews, see Hunt et al., 1991a,b; Krumlauf, 1994; Schilling, 1997; Morrison, 1998). Analysis of the patterns of expression of Hox genes in mouse embryos showed that 3 members of Hox A-D clusters are expressed in the hindbrain region before the formation of rhombomeres, and that later their patterns of expression respected rhombomeric boundaries (Krumlauf, 1994; Wilkinson, 1995). In general, with the exception of paralogous group 1 and Hoxa2, the paralogous groups have similar anterior boundaries within the hindbrain. These overlapping patterns of Hox expression have been called the Hox codes. In addition, it was shown that at least part of the overlapping patterns of Hox expression (Hox code) in each rhombomere is maintained in migratory CNCC as they populate the branchial arches, so that the branchial arches end up with a distinct pattern of Hox expression that closely resembles the Hox code of the rhombomeres from which they originated (Hunt et al., 1991a,b; Krumlauf, 1994; Wilkinson, 1995). Thus, CNCC-derived mesenchyme of the third branchial arch (similar to R6) expresses the second and third paralogous groups, and the second branchial arch mesenchyme that is colonized by CNCC from R4 expresses only the second paralogous group. These observations provide strong support for the involvement of a combinatorial Hox code in the pre-specification of CNCC giving rise to the skeletal elements of the more caudal branchial arches (2nd and 3rd arches). Direct evidence for roles of Hox genes in regulating the patterning of the CNCC-derived skeleton of the caudal branchial arches comes from skeletal abnormalities in the third and fourth branchial arches in knock-out mice lacking Hoxa3 (Chisaka and Capecchi, 1991; Manley and Capecchi, 1995, 1998). of the Hox However, with the exception of Hoxa2, none genes is expressed rostral to R3 (Wilkinson et al., 1989; Hunt et al., 1991b; Krumlauf, 1994; Prince and Lumsden, 1994; Richman, 1995). Although Hoxa2 is expressed up to the R1/R2 boundary, the most anterior Hoxa2-expressing CNCC populate the hyoid arch but not the first arch. Therefore, the first branchial arch that was shown previously to be morphogenetically specified (Noden, 1983a) is devoid of any Hox gene expression. The lack of Hox expression in the most rostral regions of the developing neural tube and in the CNCC of the first branchial arch suggested that the primary characteristic disthe first branchial arch from tinguishing the CNCC populating of Hox gene products absence the be CNCC more caudal may et et 1993; Rijli al., 1993, 1998). (Gendron-Maguire al., A predication of this model is that removal of Hoxa2 function from the CNCC populating the second branchial arch
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presence absence of Hox expression in pre-migratory CNCC while still in the neural tube, is that experimental manipulations of rhombomeres should result in colonization of the branchial arch with CNCC expressing inappropriate Hox codes and, thus, should give rise to inappropriate skeletal elements. Although the original grafting experiments of Noden (1983a) support this model, findings of more recent transplantation studies in chick embryos have provided conflicting results. The differences in the results appear to be related to the axial level of origin of crest cell, the type of experimental manipulation, and the time intervals in which Hox expression in the branchial arches has been examined. Studies in which the neural tube and pre-migratory CNCC are re-located within the hindbrain and patterns of Hox expression in the branchial arches are examined early (one day post-operatively) indicate that the grafted NCC populated the branchial arches according to their new position but maintained the patterns of Hox gene expression appropriate for their position of origin (Prince and Lumsden, 1994; Saldivar et al., 1996, 1997; Couly et al., 1998). The stability of the Hox code in crest cells in ectopic locations in some, but not all, cases was correlated with skeletal abnormalities. On the other hand, analysis of embryos in which crest cells are re-routed by late deletion of adjacent crest cells and experiments involving rotation of the entire hindbrain and its associated crest (R1-R7) indicates that the initial stable Hox code is modified within the branchial arches 2 or 3 days after transplantation (Hunt et al., 1995, 1998; Saldivar et al., 1997). In these situations, the Hox code in CNCC in ectopic locations is modified, matches their new location within the branchial arches, 278 278

if not identical to the phenotype of the chick embryo after transplantation of the presumptive first-arch CNCC into the secondarch region (Noden, 1983a). Based on the long-term fate-mapping studies in chick embryos and established homologies between mammals and birds (Kontges and Lumsden, 1996), it was concluded that the absence of Hoxa2 results in specific homeotic transformation in which the R4-derived mesenchymal cells in the hyoid arch acquired the identity of the caudal region of mandibular mesenchyme derived from Rl and R2, but not the identity of CNCC mesenchyme derived mainly from the midbrain (GendronMaguire et al., 1993; Rijli et al., 1993, 1998; Kontges and Lumsden, 1996). The phenotypic abnormalities in Hoxa2 mutants suggested essential roles for Hoxa2 in the morphogenetic identity of the second branchial arch skeletal elements consistent with postulated roles of Hox codes in patterning of the CNCC-skeletal derivatives of the more caudal branchial arch. One of the predications of the CNCC pre-specification model, in which patterning information is imprinted by the or

tion of Meckel's cartilage, dentary, maxilla, palatine, jugal bones, and teeth. The phenotype of the Hoxa2 mutant is similar

not include more proximal structures, such as the proximal por-

tory meatus (Gendron-Maguire et al., 1993; Rijli et al., 1993). However, the duplicated structures in the Hoxa2 mutants did

would lead to re-specification of second-arch CNCC identity into that of the first arch. In fact, in Hoxa2 mutants, morphogenesis of the first and second branchial arches is altered (Rijli et al., 1993; Gendron-Maguire et al., 1993). Hoxa2 mutants lack all of the skeletal elements of the second branchial arch and contain a mirror-image duplicated set of caudal mandibular skeletal elements, including a truncated Meckel's cartilage, incus, malleus, tympanic and squamosal bones, and duplicated external audi-

and gives rise to almost normal CNCC-derived skeletal components. For example, Hunt et al. (1998) showed that when the Hox-expressing R7 is placed in the Rl region, CNCC from the grafted Hox-expressing R7 together with the host mesencephalic crest cells migrate into the first branchial arch, become Hox-negative (match their new position in the first branchial arch), and give rise to normal first-arch skeletal components with some additional ectopic first-arch structures. The results of these studies suggest that the Hox code in the branchial arches can be established independently of the hindbrain after CNCC migration into the branchial arches. The modification of Hox expression in the branchial arches colonized with mixed populations of CNCC is thought to be mediated by "community effects", where the Hox code expressed by the majority of cells eventually predominates and results in either gain or loss of Hox expression (Saldivar et al., 1997; Hunt et al., 1998). Alternatively, it has been postulated that alteration in Hox expression may be mediated by environmental influences emanating from adjacent tissues (i.e., neighboring neural tube, mesoderm, and branchial arches). More recent results suggest that a Hox code, rather than being involved in pre-specification of CNCC, may be involved in the maintenance of appropriate registration of different structures within each branchial arch (Kontges and Lumsden, 1996; Hunt et al., 1998). Despite the lack of expression of 3' members of the antennapedia class of Hox genes, several other regulatory genes have been shown to be expressed in presumptive CNCC in more rostral regions of the brain and in distinct regions of CNCC-derived mesenchyme of the first branchial arch, suggestive of their involvement in the initial formation and morphogenesis of the first branchial arch. These genes include members of Msx, Dlx, Otx, Barx, Gsc, Pax, Hand, Pitx, and Prx genes. As transcription factors, they achieve this function by regulating the expression of other regulatory genes.

Outgrowth of the Mandibular Processes

Tissue recombination studies indicate that outgrowth of the mandibular processes is dependent on epithelial-mesenchymal interactions (Wedden, 1987; Richman and Tickle, 1989; Hall and Coffin-Collins, 1990; Mina et al., 1994). Following removal of the overlying epithelium, reduced outgrowth is seen in the mandibular mesenchyme, suggesting that signals derived from mandibular epithelium regulate growth of the underlying mesenchyme. In addition, tissue recombination studies in which epithelia and mesenchyme from different facial processes were exchanged suggest similarities in the signaling cascades regulating outgrowth of all the facial processes (Richman and Tickle, 1989). Outgrowth of the mandibular mesenchyme is supported by epithelia covering other facial processes, and mandibular epithelium supports the outgrowth of the mesenchyme from other facial processes. Although these recombination studies clearly indicated the mitogenic roles of mandibular epithelium on the underlying mesenchyme, they did not identify any specific regions in the epithelium or mesenchyme that may be involved in regulating the outgrowth of the developing mandible. Furthermore, the mandibular arch, similar to other facial processes, lacks clearly identifiable morphological or functional regions. Studies in the developing chick mandible suggest that a population of cells in the medial region (see Fig. 1) plays a significant role in the growth of the developing mandible. Dil labeling studies indicated that cells in the medial region make
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a greater contribution to the overall expansion of the developing mandible as compared with cells in the lateral region (McGonnell et al., 1998). Cell proliferation studies showed a high percentage of S-phase-labeled cells in the medial region (Mina et al., 1995; Barlow and Francis-West, 1997; McGonnell et al., 1998). Furthermore, when only the medial region of stage 24 mandibular arches is grown for 1 wk as a graft in the dorsal surface of a chick wing, cartilage rods of substantial length (60% of the length of the cartilage rods formed in the intact mandible at stage 37) are formed (Richman and Tickle, 1989; Mina et al., submitted manuscript). Together, these observations suggest that the medial region is a putative functional region involved in regulating directional outgrowth of the developing mandible. Interestingly, high levels of expression of many of the evolutionary conserved signaling factors and transcription factors are detected in the epithelium and mesenchyme of the medial region (see below). Direct evidence for the involvement of some of these genes in the outgrowth of mandibular processes comes from abnormalities in the developing mandibles in homozygous null mutant mice lacking these genes (knockout mice). Furthermore, some of these genes have been shown to be candidate genes causing human craniofacial disorders affecting mandibular growth and morphogenesis.

(A)

Midline
Medial (Proximal) 4
* Lateral (Caudal)

Oral

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(B()

CDP
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Transcription Factors in Mandibular Morphogenesis

Msx GENES
The vertebrate Msx gene family was originally isolated by homology to the Drosophila Msh gene (muscle segment homeobox gene) (Hill et al., 1989; Robert et al., 1989; Davidson, 1995) and consists of 3 members that are not positioned in a single gene cluster. Studies in vertebrate embryos showed that Msxl and Msx2 are expressed throughout the embryo, including the rostral region of the developing head, suggesting their involvement in craniofacial development (Davidson, 1995; Maas and Bei, 1997, and references therein). The most interesting aspect of the vertebrate Msx family is their complementary or overlapping patterns of expression in different regions of the embryo where morphogenesis has been shown to be dependent on inductive epithelial-mesenchymal interactions (Davidson, 1995; Maas and Bei, 1997). At early stages of development, the expression of Msxl and Msx2 in the mandibular arch is limited to the mesenchyme in the medial region and is excluded from the mesenchyme in the lateral region (MacKenzie et al., 1991, 1992; Nishikawa et al., 1994; Mina et al., 1995; Barlow and FrancisWest, 1997). In addition to its expression in the medial region, Msxl is also expressed in the mesenchyme surrounding the hyomandibular cleft. Tissue recombination and bead implantation studies indicate that the expression of Msx genes in the developing mandible and other facial processes is dependent on signals derived from the overlying epithelium (Takahashi et al., 1991; Brown et al., 1993, 1997; Jowett et al., 1993; Mina et al., 1995; Chen et al., 1996; Bei and Maas, 1998; Wang et al., 1998b). In the developing mandible at early stages, the expression of Msxl in the medial region is correlated with areas undergoing expansion which contain highly proliferative and undifferentiated mesenchyme cells (Mina et al., 1995). In Msxl-deficient mice, the medial part of the
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Figure 1. (A) Line drawings illustrating a frontal view of the developing mandibular arch at early stages of development, indicating thle anatomical landmarks and terminologies used in this paper. The medial (proximal region) is indicated by a hatched pattern. The lateral region is indicated by stippling, and an arrow indicates the region of the hyomandibular clef. (B) Line drawing illustratinq a lateral view of the developing mandibular arch at late stages o development, indicating the anatomical structures referred to in this study. The mandibular arch structures derived from the posterior midbrain, RI and R2, are indicated by a dotted pattern, and the skeletal elements of the hyaid arch (second branchial arch) that are derived from R4 are idicated by hatched pattern. AP, articular process; CDP, condylar process; CP, coronoid process; 1, incus; M, malleus; S, stapes; Sq, squamosal. The letters in parentheses indicate avian names for structures homologous in mammals in the middle ear region and have been adapted from Kontges and Lumsden (1996). (A) articular; (Pq) pterygoquadrate; (Q) quadrate.
mandible is truncated (Satokata and Maas, 1994). On the other hand, the domain of Msx2 expression in the lower medial region of the mandibular mesenchyme (Wedden, 1991; Mina et al., 1995; Shen et al., 1997), similar to its expression in many organs, is correlated with areas of apoptosis (Graham et al., 1996; Macias et al., 1996; Maden et al., 1997; Marazzi et al., 1997; Ferrari et al., 1998; Takahashi et al., 1998). Studies in the developing chick mandible also suggest that Msx genes may be involved in delineating the non-chondrogenic region at the midline region (symphysis). This possibility is supported by observations that, in contrast to control explants, explants from chick mandibular arches treated with Msx2 antisense oligonucleotides formed cartilage in the medial region, resulting in the
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fusion of the 2 bilateral rods of cartilage at the midline (Mina et al., 1996). More recently, it was shown that overexpression of Msx2 also inhibits chondrogenesis in organcultured mouse mandibles (Semba et al., 2000). Although lack of Msxl does not appear to disturb the mandibular symphysis, Msxl/Msx2 knock-outs display severe abnormalities in the developing mandible (Satokata et al., 2000). In humans, mutation of one copy of MSX1 results in single-tooth agenesis, and specific point mutations in the homeodomain in one copy of MSX2 result in Boston-type craniosynostosis (reviewed by Cohen, 2000).

DLX GENES
The Dlx genes constitute a highly conserved family of homeobox-containing genes, homologous to the Drosophila Distal-less (DlI) gene that is required for many processes, including the formation of the mouth (Cohen et al., 1989). In the mouse, there are at least 6 Dlx genes arranged as pairs which are convergently transcribed (Dlxl and Dlx2, Dlx3 and DIX7, Dlx5 and Dlx6) (see review by Kraus and Lufkin, 1999, and references therein). Members of the Dlx family are expressed in the craniofacial region in both ectoderm and mesenchyme (Davideau et al., 1999; Kraus and Lufkin, 1999, and other references therein). Among these, DIX2, DIX3, and Dlx5 are expressed at the junction of the neural plate and surface ectoderm, suggesting that they may be expressed by pre-migratory and migratory CNCC cells (Robinson and Mahon, 1994; Qiu et al., 1997; Yang et al., 1998; Acampora et al., 1999; Depew et al., 1999). In situ hybridization studies on E9.5-E1O mouse embryos showed that Dlxl and Dlx2 are expressed in the mesenchyme of both proximal and distal regions of all branchial arches, while DIX3, DIX5, and DIx6 are expressed predominantly in mesenchyme of the distal regions (reviewed by Kraus and Lufkin, 1999). For example, in the first branchial arch, Dlxl and Dlx2 are expressed in the maxillary processes (the proximally located component) as well as in the mandibular processes (the distally located component) and Dlx3, Dlx5, and Dlx6 are expressed only in the mandibular processes. In the developing mandible, Dlx genes are expressed in a lateral-to-medial gradient. Similarly, in the second (hyoid) arch, Dlxl and DIx2 are expressed throughout the proximo-distal axis, while DX3, Dlx5, and Dlx6 are expressed only in the more distal (close to the mid-

mandibles of Dlx5 mutant mice are shortened, lack the coronoid process, and contain misshapen condylar and angular processes. The phenotypic abnormalities in the mandibular arches of Dlx5 mutants suggest essential (non-redundant) roles of Dlx5 for proper development of mandibular processes and the skeleton of the caudal region of the mandibular arch. Further analyses of the branchial arches in Dlx5 mutants indicate that the absence of Dlx5 did not affect cell proliferation or apoptosis but expanded the territory of the proliferating cells within the first branchial arch (Acampora et al., 1999). In situ hybridization analysis indicated decreases of Goosecoid (Gsc) expression in the mesenchyme of the frontonasal processes and in the mandibular and hyoid mesenchyme of the Dlx5 mutants (Depew et al., 1999). Unlike other members of the Dlx family, Dlx5 and Dlx6 are also expressed in developing bones, cartilage, and teeth, suggesting that the Dlx5 and Dlx6 genes may play roles in the multi-step process of skeletal differentiation and/or morphogenesis (Zhao et al., 1994a; Ferrari et al., 1995; Newberry et al., 1998; Acampora et al., 1999; Davideau et al., 1999; Depew et al., 1999). Dlx5 is also expressed at specific stages of osteoblast differentiation in vitro and could repress osteocalcin gene expression (Ryoo et al., 1997). Interestingly, lack of Dlx5 results in hypo-mineralization of calvaria (Acampora et al., 1999; Depew et al., 1999) and expression of osteocalcin in the periosteum at birth (Acampora et al., 1999). In humans, there is evidence implicating DLX5 and DLX6 genes as candidate genes for ectrodactyly (split hand/foot malformations, SHFM1) (Scherer et al., 1994; Crackower et al., 1996). Often, these patients also have cleft palate and deafness (Ignatius et al., 1996). A frame-shift mutation in DLX3 is also associated with taurodontism and enamel hypoplasia in humans with Tricho-dento-osseous syndrome (Price et al., 1998).

OTX- GENES Another family of evolutionary conserved homeodomain factors with critical regulatory roles in the determination of head structures during development is the Otx genes, vertebrate homologs to Orthodenticle in Drosophila (for review, see BallyCuif and Boncinelli, 1997; Simeone, 1998; Acampora et al., 2000).

However, in these mutants, the skeletal components of the mandibular arch and distal hyoid arch appeared to be normal
one of the most noticeable abnormalities in the mice homozygous for a targeted deletion of Dlx5 is in the developing

mice lacking Dlxl, Dlx2, Dlxl/Dlx2, and DIx5. Mice lacking Dlxl, Dlx2, and Dlxl/Dlx2 exhibited abnormalities similar, but not identical, to those of maxillary and proximal (caudal) hyoid archderived structures (Qiu et al., 1995, 1997; Thomas et al., 1997).

line) region of the second arch. These patterns of expression suggested that Dlx genes play essential roles in proximo-distal patterning of the branchial arches (Qiu et al., 1997). This possibility is supported by phenotypic abnormalities in

Acampora et al., 1996, 1998).

et

The overlapping patterns of expression of Otx and Emx genes in the rostral region of the developing brain, together with functional studies, have suggested that these genes, analogous to the Hox code for hindbrain development, provide a combinatorial code for rostral brain development (for reviews, see Bally-Cuif and Boncinelli, 1997; Simeone, 1998; Acampora et al., 2000). Otx2 homozygous null mutants die early in embryogenesis and fail to develop structures anterior to R3 (Acampora et al., 1995; Matsuo et al., 1995; Ang et al., 1996). The phenotypic abnormalities in Otxl homozygous mutants indicated its essential role in the formation of cortex in the adult brain (Suda et al., 1996;
In addition to its expression in the rostral region of the

(Qiu et al., 1995, 1997; Thomas et al., 1997). On the other hand,

stages (E13-E14), the mandibular arch and the Meckel's cartilage of Dlx5 mutants are shorter than those in wild-type embryos and exhibit abnormalities in the caudal region of Meckel's cartilage. At its caudal end, Meckel's cartilage in DIx5 mutants is bifurcated and gives rise to an ectopic novel cartilage, which becomes surrounded by bone later in development. At birth, the 280

mandible (Acampora et al., 1995; Depew et al., 1999). At early

from the forebrain up to the mid-hind-brain isthmus (Matsuo al., 1995; Ang et al., 1996). Interestingly, Otx2 heterozygote animals exhibit otocephaly and abnormalities in midbrain crest derivatives of the first arch, suggesting a role for Otx2 in pre-migratory CNCC originating from the midbrain region (Matsuo et al., 1995). In Otx2+/- mice, the elements that were shown to be derived solely from midbrain crest (distal Meckel's cartilage, dentary, maxilla, and palatine) (Kontges and Lumsden, 1996) are lacking or severely reduced, suggestBiol
Med

developing brain, Otx2 is also expressed in neuroectoderm

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ing that defects in these animals may be due to deficiencies in CNNC derived from the midbrain region. However, in Otx2+/mice, the hindbrain-derived, first-arch elements (malleus, incus, and pterygoid) are almost unaffected. Analysis of the knock-in mice in which Otx2 was replaced with Otxl showed that most Otx2 functions, including the Otx2 haploinsufficiency causing the otocephalic phenotype, are replaceable with those of Otxl (Suda et al., 1999).

GOOSECOID
Goosecoid (Gsc) encodes another evolutionary conserved pairedlike homeoprotein that acts as a transcription factor with essential roles in head development (for review, see Bally-Cuif and Boncinelli, 1997). In vertebrates, Gsc is expressed transiently at the rostral end of the developing brain and then re-appears at E9.5-E10.5 in many sites, including the mesenchyme of the branchial arches (Gaunt et al., 1993; Rivera-Perez et al., 1995, 1999; Yamada et al., 1995, 1997). In the mandibular arch, Gsc is strongly expressed in the mesenchyme in the region of the hyomandibular cleft. Gsc null mutants die soon after birth, with rib cage malformations and multiple craniofacial defects, including abnormalities in the mandibular arch and middle ear structures (RiveraPerez et al., 1995, 1999; Yamada et al., 1995,1997). In the mandibles of these mutants, although the condylar process appears normal, the coronoid and angular processes are severely reduced in size, and the mandible is shortened in length. Furthermore, Meckel's cartilage is not enclosed by the mandibular bones but is embedded in a novel groove that extends along the entire length of the mandible. Recent studies showed that abnormalities in the mandible of Gsc null mutants are due to the absence of cells destined to express Gsc in these mutants, suggesting the essential roles of Gsc in the initial proliferation and/or survival of Gscexpressing cells (Rivera-Perez et al., 1999).

PITX GENES
Pitxl (Ptxl /POTX) and Pitx2 (RIEG, Otx2, Otlx2, Brxl, Arpl) are 2 members of a vertebrate multigene family with overlapping and distinctive patterns of expression during embryogenesis (for reviews, see Drouin et al., 1998; Gage et al., 1999; Meijlink et al., 1999, and references therein). Pitxl was originally identified as a factor interacting with the pituitary-specific transcription factor Pit-i and POMC promoter (see reviews). Pitxl is expressed in the pituitary gland throughout its development, in the lateral plate mesoderm of the caudal half of the embryo which leads to its expression exclusively in the hindlimb and not the forelimb, in the first branchial arch and its derivatives, and in oral ectoderm (Szeto et al., 1996; Lanctot et al., 1997; Meijlink et al., 1999). The patterns of expression suggest that Pitxl is a critical transcription factor involved in specification of the hindlimb and development of the pituitary gland and structures derived from the first branchial arch. This possibility was supported by phenotypic abnormalities in null mutants for Pitxl and mis-expression of Pitxl in the chick wing bud (Lanctot et al., 1999; Logan and Tabin, 1999; Szeto et al., 1999). Pitxl null mutants die immediately or shortly after birth and are readily recognizable by their shortened mandibular arch. These mutants exhibit abnormalities in the limb and in the derivatives of the first branchial arch, including cleft palate, significantly shortened tongue and mandible, a novel bone surrounding Meckel's cartilage, and lack of gonial bones (Lanctot et al., 1999; Szeto et al., 1999). In situ hybridization analysis indicated that the expression of several markers expressed early in the first
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branchial arch-including Msxl, Msx2, Gsc, Shh, Bmp2/4, Wnt5a, and Pitx2-is unaltered in Pitxl null mutant mice (Szeto et al., 1999), suggesting that defects in the craniofacial structures similar to those observed in the hindlimb may be due to defects in proliferation and/or abnormal chondrogenesis of mesenchymal cells (Lanctot et al., 1999; Szeto et al., 1999). Interestingly, it has been suggested that, in humans, mutant PITX1 alleles might be responsible for a subset of patients with Treacher-Collins syndrome (Crawford et al., 1997). Pitx2/RIEG was initially identified by positional cloning of the gene responsible for Rieger Syndrome in humans (Semina et al., 1996; Gage and Camper, 1999; Meijlink et al., 1999). This autosomaldominant haploinsufficiency syndrome is characterized by anterior chamber ocular abnormalities and other features of various degrees of severity, including dental hypodontia, umbilical abnormalities, cardiac defects, and mild craniofacial dysmorphism. Pitx2 is expressed in many tissues during development, including the craniofacial mesenchyme and epithelium of the first and second branchial arches (see review by Meijlink et al., 1999, and references therein). Experimental evidence indicated a role for Pitx2 downstream of sonic hedgehog and nodal in a genetic pathway regulating laterality of heart, gut, and other asymmetric organs (see review by Meijlink et al., 1999, and references therein). The direct role of Pitx2 in left-right determination and development of other structures, including the development of the mandibular and maxillary processes, is provided by abnormalities in mice deficient for Pitx2 (Gage et al., 1999; Lin et al., 1999; Lu et al., 1999b). Pitx2 mutant mice die at around E14-15 and exhibit lung isomerization and defects in cardiac positioning and pituitary development (Lin et al., 1999; Lu et al., 1999b). In addition, Pitx2 null mutants exhibited cleft palate and abnormalities in the maxillary and mandibular arches, including severely hypoplastic mandible and arrested tooth buds (Lin et al., 1999; Lu et al., 1999b). In situ hybridization analysis indicated the absence of Fgf8 and altered domains of expression of Bmp4, Msxl, and Msx2 in the developing facial processes in Pitx2 null mutants, suggesting that the facial abnormalities may be mediated by changes in the patterns of expression of these genes (Lin et al., 1999; Lu et al., 1999b).

PAX GENES
Pax genes encode a family of transcription factors characterized by an evolutionary conserved paired box domain, a 384-bp DNAbinding motif that regulates embryonic development by the control of target genes (for reviews, see Balling et al., 1996; Dahl et al., 1997; Peters et al., 1998a; Mansouri et al., 1999, and references therein). In mammals, the Pax gene family consists of 9 members that, based on the presence or absence of structural motifs, are divided into 4 subgroups (see above reviews). Genes within an individual group show a very high degree of sequence similarity within the paired domain and exhibit similar patterns of expression during embryogenesis (Dahl et al., 1997). The roles and functions of Pax genes in embryonic development have been elucidated by analysis of naturally occurring mouse mutants, targeted inactivation of several Pax genes in mice, and human syndromes (see above reviews). A common feature of all Pax mutants is

reduction in size and malformation or loss of specific organs. Among all Pax genes, members of group I (Paxl, Pax 9), group III (Pax3, Pax 7), and group IV (Pax 6) are expressed in the developing facial processes (Peters et al., 1998a; Mansouri et al., 1999). Analyses of various mutants have indicated essential roles for Pax3, Pax6, and Pax7 in the development of CNCC-derived structures in the upper face (for reviews, see Peters et al., 1998a;
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Mansouri et al., 1999; Francis-West et al., 1998). However, in these mutants, no abnormalities were observed in CNCC-derived structures of the lower face. On the other hand, phenotypic abnormalities in the Pax9 null mutant (Peters et al., 1998a,b) indicate essential roles for Pax9 for the lower face. Pax9-deficient mice lacked structures derived from pharyngeal pouches, such as thymus and parathyroid glands. In the developing mandible, in addition to abnormalities in the developing teeth, the alveolar ridge and the coronoid process are absent in Pax9 null mutants.

(previously called S8) related of members the closely paired-related family of homeobox genes that are co-expressed in a variety of sites, including the craniofacial mesenchyme (see review by Meijlink et al., 1999, and references therein). Studies in developing mice and chickens indicate that Prxl and Prx2 are co-expressed in the CNCC-derived mesenchyme of the frontonasal process, in the mesenchyme of the first and second branchial arches, and in the pre-osteogenic areas. In the developing mandible, at early stages of development, high levels of expression of both genes are detected in the mesenchyme of the medial region. In addition to the medial region, Prxl is also expressed in the cells around the first branchial groove. As development proceeds, the expression of both genes is downregulated in the mandibular process but maintained in the maxillary and nasal processes (Lu et al., 1999a). Although Prx2 null mutant mice show no obvious craniofacial and skeletal abnormalities (ten Berge et al., 1998), Prxl null mutant mice show defects in skeletal elements derived from the maxillary processes and the caudal part of the mandibular processes, including hypoplastic coronoid, condylar, and angular processes and malformed malleus (Martin et al., 1995). In addition, Meckel's cartilage in Prxl mutants displayed abnormal sigmoidal morphology (Martin et al., 1995). More recent studies (Lu et al., 1999a) indicate that, in the Prxl null mutants, cells fated to express Prxl are initially present in the regions that give rise to the defective structures, but disappear later, suggesting that Prxl product may be required for the maintenance (proliferation and/or survival) of specific subpopulations of CNCC-derived mesenchymal cells in the branchial arches. In contrast to single mutants, Prxl/Prx2 double-knock-out mice exhibited severe craniofacial abnormalities, including pointed snout, the absence of external ears, and severely shortened lower jaws (ten Berge et al., 1998; Lu et al., 1999a; Meijlink et al., 1999). Double-mutant mice also had novel phenotypes, including abnormalities in the medial region of the developing mandibles, lower incisors, and Meckel's cartilage (ten Berge et al., 1998; Lu et al., 1999a; Meijlink et al., 1999). Approximately 8% of the newborn double-mutants generated by ten Berge et al. (1998) exhibited clefts in the mandible and tongue, whereas the mandibular processes of the double-mutant mice generated by Lu et al. (1999a) lacked the midline symphysis and were fused. In these double-mutants, either a single incisor arrested in the bud stage or no incisors were present. The arrested incisor tooth buds showed decreases in the expression of Pax9 and patched (Lu et al., 1999a; Meijlink et al., 1999). Furthermore, in these doublemutants, most of Meckel's cartilage was absent (ten Berge et al., 1998; Lu et al., 1999a; Meijlink et al., 1999). In situ hybridization analysis showed that, in double-mutants, Sox9 (a marker of prechondrogenic mesenchyme of the branchial arches) was expressed normally in the area of the pre-chondrogenic condenare

PRX GENES Prxl (previously called Mhox) and Prx2

sation of Meckel's cartilage, suggesting that, in the absence of Prxl and Prx-2, the pre-chondrogenic condensation of Meckel's cartilage is initiated but is not maintained (Lu et al., 1999a). The phenotypic abnormalities in Prxl and Prxl/Prx2 mutants indicate redundant but essential roles for Prxl and Prx2 in the signaling network regulating epithelial-mesenchymal interactions that promote outgrowth and skeletogenesis in the lower jaw. Other members of the paired-related family of homeobox genes in vertebrates include Alx3, Alx4, and Cartl (Meijlink et al., 1999). These genes are also expressed in the distal part of the mandibular arch (Zhao et al., 1994b; Qu et al., 1997a,b; ten Berge et al., 1998). However, no phenotypic abnormalities in the developing mandible have been reported in mice lacking these genes (Zhao et al., 1994b; Qu et al., 1997a). It is possible that, similar to Prxl and Prx2, the absence of abnormalities in the mandibular arch in these knock-outs may be due to functional redundancies.

BARX GENES
Barxl and Barx2 are 2 members of the vertebrate Bar class of

homeobox-containing genes homologous to Drosophila BarHl and BarH2 (Higashijima et al., 1992a,b; Kojima et al., 1991). Three mouse and 2 chick homologues of the Barx genes have been isolated (Tissier-Seta et al., 1995; Jones et al., 1997; Saito et al., 1998; Barlow et al., 1999; Smith and Tabin, 1999). Tissue distribution studies showed that these genes are expressed in many sites, including the facial processes (Tucker et al., 1989b; Tissier-Seta et al., 1995; Jones et al., 1997; Mitsiadis et al., 1998b; Barlow et al., 1999; Smith and Tabin, 1999). Studies in developing mice showed that, in the developing maxilla and mandible, Barxl is expressed in the mesenchyme (Tissier-Seta et al., 1995; Jones et al., 1997; Mitsiadis et al., 1998b; Tucker et al., 1998b), and Barx2 is expressed in the overlying epithelium (Jones et al., 1997). However, studies in chick embryos indicate that, unlike in the mouse, Barxl is expressed in both epithelium and mesenchyme of the maxillary and mandibular processes (Barlow et al., 1999). Furthermore, in chick embryos, Barx2b-which is 80% and 61% identical to mouse Barx2 and Barxl, respectively-is expressed prominently in myogenic populations in the craniofacial region,
in the mesoderm of the branchial arches, and in areas of the

forming bones (Smith and Tabin, 1999). At stage 25, Barx2b is expressed at the tips of the outgrowing maxilla and mandible but disappears by stage 30 (Smith and Tabin, 1999).
In both the chick and mouse, the mesenchymal domain of Barxl expression is restricted to the lateral region, where Fg,f8 is expressed by the overlying epithelium (Tucker et al., 1998b; Barlow et al., 1999). The expression of Barxl is excluded from the mesenchyme in the medial region in which Bmp4 is expressed in the overlying epithelium (Tucker et al., 1998b; Barlow et al., 1999). The expression of Barxl is also excluded from the central core corresponding to the regions forming Meckel's cartilage and the muscle of the mandibular process (Tissier-Seta et al., 1995; Barlow et al., 1999). These patterns of expression suggest the involvement of signals derived from the overlying epithelium (Fibroblast growth factor-8 and Bone Morphogenetic proteins) in regulating the spatial patterns of Barxl expression in the mandibular mesenchyme. In fact, studies in mouse mandibles indicate that beads soaked in FGF8 can induce/maintain expression of Barxl in the lateral mandibular mesenchyme (Tucker et al., 1998b). On the other hand, beads soaked in BMP-4 inhibited expression of Barxl in the lateral mandibular mesenchyme expression

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(Tucker et al., 1998b). Inhibition of BMP4 signaling by application of Noggin protein during the early stages of mandibular development resulted in ectopic expression of Barxl in the mesenchyme in the medial region (Tucker et al., 1998b). Similar antagonistic interactions between BMP and FGF signaling also restrict expression of Barxl to the maxillary mesenchyme in the posterior region (Barlow et al., 1999), suggestive of the involvement of Barxl in patterning of the facial processes.

Secreted Factors in Mandibular Morphogenesis

Secreted factors involved in mandibular outgrowth and morphogenesis include members of the fibroblast growth factor (FGFs), transforming growth factor beta (TGF3), and hedgehog families, Wnt genes, endothelin pathway, notch pathway, and epidermal growth factor.

BONE MORPHOGENETIC PROTEINS (BMPS)

The transforming growth factor-beta (TGFI) superfamily is composed of more than 30 members and has been divided into several subgroups based on the extent of homology in the mature ligand (for review, see Hogan, 1996; Wozney, 1998). The largest subgroup constitutes the bone morphogenetic proteins (BMPs). In mammals, there are at least 12 BMPs that have been implicated in the development of almost all vertebrate organs and are thought to be important mediators of inductive tissue interactions during embryogenesis (Hogan, 1996; Wozney, 1998). The actions of TGF3s are mediated by the TGF3 receptors. These serine/threonine receptor kinases fall into 2 classes, type I and type II receptors (for review, see Kawabata et al., 1998; Massague, 1998; Raftery and Sutherland, 1999). Ligand binding leads to the formation of heterodimers of these 2 receptor types, phosphorylation of the type I receptor by the type II receptor, and subsequent propagation of the intracellular signal. Seven type I or activin-like kinases (ALKs) and 5 type II receptors have been identified in vertebrates (Massague, 1998). Among these, BMPR1A (ALK-3), BMPR1B (ALK-6), and ActR 1 (ALK-2) appear to be essential for BMP signals (Hogan, 1996; Massague, 1998). Different BMP ligands are capable of activating common signaling pathways (for review, see Massagu6, 1998). Ligands in the TGFI superfamily are active as dimers, and the subunit composition of these molecules can dramatically affect signaling activity. Although BMP heterodimers have yet to be identified in vivo, BMP heterodimers made in vitro (BMP-4/BMP-7 and BMP-2/BMP-7) show more potent biological activity than BMP homodimers (Aono et al., 1995; Israel et al., 1996; Suzuki et al., 1997; Tsuji et al., 1998). In addition, Smads are essential for TGFJ-related signal transduction. Smad-1, Smad-5, and Smad-8 proteins (reviewed by Kretzschmar and Massague, 1998; Miyazono, 1999) are BMP receptor substrates, and Smad 2 and Smad 3 are substrates for the related TGF3 and activin receptors in vertebrate (Kretzschmar and Massague, 1998; Miyazono, 1999). Tissue distribution studies showed that multiple Bmps (Bmp-2, -4, -5, and -7) are expressed in the epithelium of the mandibular arch (Francis-West et al., 1994; Wall and Hogan, 1995; Aberg et al., 1997; Barlow and Francis-West, 1997; Tucker et al., 1998a; Wang et al., 1998b, 1999; Solloway and Robertson, 1999). At early stages, expression of Bmp-4 and Bmp-5 is restricted to the epithelium of the medial region overlying the Msxl and Msx2 expressing mesenchyme. In contrast to the restricted patterns of expression of these Bmps, Bmp-2 and Bmp-7 are expressed in a broader domain throughout the epithelium of the branchial arches. Furthermore, similar to the effects of mandibular epithelium in tissue recombination experiments, agarose beads soaked in BMP-2, -4, or -7 are able to maintain cell proliferation and Msx expression in the medial mandibular mesenchyme (Barlow and Francis-West, 1997; Wang et al., 1998b, 1999). When placed laterally, BMPs induced cell proliferation and ectopic expression of Msx expression in the lateral mandibular mesenchyme, where Msx genes are not
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HAND GENES
dHAND and eHAND (Cserjesi et al., 1995; Srivastava et al., 1997; Thomas et al., 1998), 2 members of the bHLH (basic helixloop-helix) family of transcription factors, are co-expressed in many regions, including the medial region of the developing mandible. Deletion of the dHAND gene in mice resulted in embryonic death at Ell secondary to cardiac failure and many abnormalities, including severely hypoplastic first and second branchial arches (Srivastava et al., 1997; Thomas et al., 1998). Molecular analyses indicated that although Prxl, Dlx2, eHand, and Msx2 were expressed at normal levels, Msxl expression was not detectable in the medial region of the developing mandible of E9.5 dHAND null mutants (Thomas et al., 1998). These results also indicate that the hypoplastic mandible in the dHand-/- mutant is not due to defects in the migration of neural crest cells into the branchial arch and occurs secondary to programmed cell death. The unchanged patterns of expression of eHAND in the dHAND mutant suggest that eHAND is unable to compensate fully for dHAND in the branchial arch and that these genes may have some unique roles in the development of the developing mandible (Thomas et al., 1998).

OTHER TRANSCRIPTION FACTORS

Other transcription factors that have been shown to have a role in facial development are twist, ski, and AP-2, Tbx2, Tbx3, and TCOF1/Freacle. Twist is expressed at high levels in the mesenchyme of the first branchial arch, and twist null mutants exhibit abnormalities in branchial arch formation (Chen and Behringer, 1995; Gitelman, 1997). AP-2 is expressed in the cranial neural crest, and mice lacking Ap-2 had severe craniofacial abnormalities (for review, see Morriss-Kay, 1996; also see Shen et al., 1997; Zhang et al., 1996). However, in Ap-2 knock-out, similar to ski knock-out, the mandibular arch skeleton is less affected than the skeleton of the upper face (reviewed by Morriss-Kay, 1996; Berk et al., 1997). Tbx2 and Tbx3 are 2 members of the T-box family that are expressed in the mesenchyme of the maxillary and mandibular processes (Chapman et al., 1996; Gibson-Brown et al., 1998a,b; Isaac et al., 1998). TCOF1/treacle was initially identified as the gene responsible for Treacher-Collins syndrome, the most common autosomal-dominant inherited human mandibulofacial disorder characterized by cleft palate and abnormalities in the ear and of some skeletal structures derived from the first arch (Gladwin et al., 1996; Dixon et al., 1997a,b; Wise et al., 1997; Winokur and Shiang, 1998). The murine homologue of the TCOF1 gene has been isolated (Dixon et al., 1997b; Paznekas et al., 1997) and shown to be expressed in a wide variety of embryonic and adult tissues of the mouse, including the developing branchial arches at the time of critical morphogenetic events. The phenotypic abnormalities resulting from the targeted inactivation of TCOF1 should reveal its role in Treacher-Collins syndrome.
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normally expressed (Barlow and Francis-West, 1997; Wang et al., 1998b, 1999). However, unlike the mandibular epithelium, laterally or medially placed BMPs did not support the elongation of stage 23 chick mandibular mesenchyme and Meckel's cartilage (Wang et al., 1999). Further insight into the roles of BMPs in outgrowth and morphogenesis of the developing mandible comes from studies in which beads soaked in BMPs were implanted in vivo at different stages into different regions of the developing chick mandible (Barlow and Francis-West, 1997; Ekanayake and Hall, 1997; Wang et al., 1999; Mina et al., submitted manuscript). Although application of BMP-2, BMP-4, and BMP-7 for 7 to 10 days to the lateral region of a stage 23 chick mandible did not affect the growth of the mandibular mesenchyme, it did induce changes in the morphology and patterns of the skeletal elements in the caudal region (jaw joint) of mandibles on the implanted side. In contrast to their effects at stage 23, in vivo implantation of beads soaked in similar concentrations of BMPs into the lateral region of stage 20/22 mandibles exerted negative effects, resulting in reduced growth of the mandibular process and complete loss of Meckel's cartilage and its articulating elements on the implanted side (Barlow and FrancisWest, 1997; Ekanayake and Hall, 1997; Mina et al., submitted manuscript). On the other hand, implantation of beads soaked in BMPs into a more medial position (closer to the Msxexpressing mesenchyme in the medial region) of stage 20/22 mandibles induced the formation of an additional outgrowth from the body of Meckel's cartilage (Barlow and Francis-West, 1997, Mina et al., submitted manuscript). Analysis of these data indicates that chick mandibular mesenchyme from different regions (lateral vs. medial) at different stages (20 vs. 23) responds differently to BMPs. In contrast to the observations in the chick mandible, a recent study showed that application of beads soaked in 100 ng/pL for 6 days to the lateral region of organ-cultured mouse mandibles (E10) induced ectopic cartilage (Semba et al., 2000). However, BMP beads applied to the medial region did not induce ectopic cartilage (Semba et al., 2000). The overlapping patterns of expression of Bmps in mandibular epithelium and the similarities between the effects of BMPs on the mandibular mesenchyme suggest cooperative or redundant roles for BMPs in signaling cascades mediating epithelial-mesenchymal interactions regulating outgrowth and morphogenesis of the developing mandible. However, the roles of BMPs in the outgrowth of the mandibular arch remain unclear. On the one hand, the formation of an ectopic outgrowth from the body of Meckel's cartilage after implantation of BMPbeads to the medial region at stage 20/22 suggests that BMPs, through their interactions with target genes such as Msxl and Msx2, may be involved in the outgrowth and morphogenesis of the tip of the developing mandible. The phenotypic abnormalities in the Bmp-5/Bmp-7 double-knock-out (Solloway and Robertson, 1999) provide direct evidence for the involvement of BMPs in outgrowth of the mandibular arch. Previous studies demonstrated that loss of either Bmp5 or Bmp7 has no apparent effect on the development of the mandibular arch (Kingsley et al., 1992; King et al., 1994; Dudley et al., 1995; Luo et al., 1995; Dudley and Robertson, 1997). However, unlike the single null mutants, Bmp-5/Bmp-7 compound mutants display abnormalities in many organs in which Bmp5 and Bmp7 are coexpressed, including the first branchial arch (Solloway and
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Robertson, 1999). The first branchial arches in double-mutants were smaller than those in the wild-type, and displayed increased apoptosis in the surface ectoderm at the base of the arch. Analysis of the patterns of expression of twist and AP2 showed defects in the mesodermally derived tissues, suggesting that Bmp5 and Bmp7 are necessary for the maintenance/ survival of mesodermally derived cells in the first branchial arch (Solloway and Robertson, 1999). However, the negative effects of BMPs on the outgrowth of the stage 20/22 chick mandibular arch, and their inability to support outgrowth of stage 23 chick mandibular mesenchyme (Barlow and Francis-West, 1997; Ekanayake and Hall, 1997; Wang et al., 1999), suggest that BMPs, similar to their roles in outgrowth of the developing limb (Pizette and Niswander, 1999), may in fact be involved in limiting the outgrowth of the mandibular process, and that other growth factors may act cooperatively with BMPs to promote the directed outgrowth of the mandibular mesenchyme. Furthermore, since all BMPs also induced cell death in the
lateral mandibular mesenchyme (Ekanayake and Hall, 1997; Barlow and Francis-West, 1998; Wang et al., 1999), and BMP-2 inhibited chondrogenesis of the mandibular mesenchyme in vitro (Ekanayake and Hall, 1997), it is possible that deficiencies in the outgrowth of the mandibular arch may be either due to cell death and/or secondary to the inhibitory effects of BMPs on chondrogenesis and elongation of Meckel's cartilage that are thought to regulate the growth of the mandible (Ekanayake and Hall, 1997). Essential roles for members of the TGF3 family in mandibular morphogenesis are also supported by phenotypic abnormalities in Activin /3A and ActRcII knock-outs (Matzuk et al., 1995a,b,c).

FAMILY OF FIBROBLAST GROWTH FACTORS (FGFs)

The FGFs consist of a family of 18 low-molecular-weight polypeptide growth factors (for reviews, see Naski and Omitz, 1998; Szebenyi and Fallon, 1999). The actions of FGFs are mediated by FGFRs, a family of 4 transmembrane receptors with ligand-induced tyrosine kinase activity (for reviews, see Szebenyi and Fallon, 1999; Klint and Claesson-Welsh, 1999). The FGFRs are similar in their overall structural organization and consist of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. The extracellular ligand-binding domain contains 3 immunoglobulin-like (Ig-like) domains, a heparin-binding domain, and a stretch of 7 conserved acidic amino acids (acidic box). Alternative splicing of the FGF receptor mRNAs generates several different variants of the receptors that are either soluble or membrane-anchored and have different ligand-binding properties. The functionally critical splicing event results in the differential exon usage in the region coding the carboxyl-terminal half of the third Ig-like domain. The third Ig-like domain in all but FGFR-4 is encoded by 3 exons designated as A-C that are alternatively spliced. Receptors containing the region encoded by exon A are secreted and may interfere with FGF signal transduction. Receptors containing the region encoded by exon B or C differ in their ligand-binding properties and tissue distribution. In general, the B form appears to be expressed in epithelial cells and the C form in mesenchymal cells. There is compelling experimental evidence that interactions between the members of the FGF and FGFR families have important roles in mediating epithelial-mesenchymal interactions during embryogenesis (for reviews, see Burke et
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al., 1998; Martin, 1998; Hogan, 1999). Similar to the Bmps, several Fgfs, including Fgf-2, Fgf-4, Fgf8, and Fgf-9, are expressed in facial processes and the mandibular arch (Niswander and Martin, 1992; Heikinheimo et al., 1994; Crossley and Martin, 1995; Mahmood et al., 1995; Wall and Hogan, 1995; Barlow and Francis-West, 1997; Richman et al., 1997; McGonnell et al., 1998; Kettunen and Thesleff, 1998; Kettunen et al., 1998; Colvin et al., 1999). Whereas Fg,f-2 and Fgf9 are expressed throughout the mandibular epithelium, Fgf-8 and Fgf-4 are expressed in restricted regions. Although Fgf-1, Fgf-5, Fgf-12, and Fgf-10 are expressed in mouse craniofacial mesenchyme, detailed expression patterns for these genes have not yet been reported (Hebert et al., 1990; Haub and Goldfarb, 1991; Hartung et al., 1997). Fgf-13, Fgf-17, and Fgf-18 are not expressed in the facial processes of mouse embryos (Hartung et al., 1997; Maruoka et al., 1998). Fgr genes are also expressed in the developing mandible (Orr-Urtreger et al., 1991, 1993; Peters et al., 1992, 1993; Wilke et al., 1997; Kettunen et al., 1998). Fgfr2b (KGFR) is expressed in the mandibular epithelium, and Fgfrlc, Fg2c, both isoforms of Fgfr3, and Fgfr4 in the mandibular mesenchyme. At early stages, both isoforms of Fffrl (flg, cek-1), Fgfr3 (cek-2), and Fgr2c (bek, cek-3) are expressed uniformly throughout the mandibular mesenchyme. However, at later stages of development, Fgfr-2c and Fgfr3 are no longer expressed uniformly and are expressed in restricted regions (Orr-Urtreger et al., 1991; Wilke et al., 1997; Mina et al., submitted manuscript). High levels of expression of both genes are seen in the mesenchyme in the lower border of the mandible that surrounds the hyomandibular cleft. Expression of Fgfr2c but not Fgfr3 also extends to the mesenchyme in the medial region. At the time of initiation of chondrogenesis, Fgfr2c and Ffr-3 are expressed in the condensing mesenchyme of Meckel's cartilage, and Fe4 is expressed in the developing muscles (Kettunen et al., 1998). Similar to BMPs, FGFs can also mimic many effects of mandibular epithelium on the mandibular mesenchyme in vitro. In the absence of mandibular epithelium, FGF-2 and FGF-4 can maintain expression of Msxi and Msx2 in the mesenchyme of the medial region (Mina et al., 1999, submitted manuscript). In vitro studies indicate that, in contrast to BMPs, in the absence of mandibular epithelium, locally applied FGFs can partially or completely support outgrowth of the mandibular mesenchyme and Meckel's cartilage (Richman et al., 1997; Mina et al., 1999, submitted manuscript). Application of beads soaked in recombinant FGF-2 and FGF-4 to the medial (but not lateral) region of isolated stage 24 mandibular mesenchyme stimulated increases in the length of Meckel's cartilage. The cartilage rods formed in FGF-treated grafts were 60% or almost the same length as those formed in homotypic recombinations. Taken together, these observations suggest essential roles for FGFs/FGFR2c (the only receptor with high levels of expression in the mesenchyme in this region) in the mediation of epithelial-mesenchymal interactions in the medial region of the developing mandible. Based on their patterns of expression in vivo, FGF-2, FGF-4, and FGF-9 (but not FGF-8) are likely endogenous candidates for mediating the growth-promoting effects of mandibular epithelium from the medial region. Furthermore, it has been shown that Fgfr2c binds with high affinity and transmits mitogenic signals from FGF-1, -2, -4, and -9 (for review, see Szebenyi and Fallon, 1999). However, the phenotypes of Fgfr2 null mutants suggest
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that Fgfr2c may not have an essential role in the initial formation of mandibular processes (Arman et al., 1998; Xu et al.,

1998). Despite the lack of detailed descriptions of the craniofacial structure, apparently a normal mandibular process forms in E10 mice that express a hypomorphic allele of Fgfr2 (Xu et al., 1998). On the other hand, transgenic expression of the extracellular ligand-binding domain of Fgfr2b (KGER) (the isoform that is expressed in the epithelium of facial processes), which acts as a dominant-negative receptor of FGFR2b, resulted in the development of smaller faces, suggestive of the involvement of FGFR2b in craniofacial development (Celli et al., 1998). Until recently, the roles of FGF-8 in mandibular morphogenesis were not fully understood. Previous studies in mouse embryos indicate that Fgf8 is expressed in regions of the embryos where epithelium is known to direct outgrowth (Crossley and Martin, 1995). Studies in the chick face also showed correlations of the patterns of expression of Fgf-8 in the epithelium of developing facial processes with areas where mesenchyme undergoes the greatest expansion and which express high levels of Msxl (McGonnell et al., 1998). However, unlike its patterns of expression in other facial processes, Fgf8 is expressed in the epithelium in the lateral but not the medial region of the developing mandible. Studies in mice suggest that FGF-8 may be involved in the establishment of the oral-aboral polarity of the developing mandible (Tucker et al., 1999). A recent study in which Fgf8 was inactivated in the epithelium of the first branchial arch of transgenic mice by means of Cre/lox technology has provided direct evidence for roles of FGF8 in the development and morphogenesis of the lateral (but not medial) regions of the developing mandible (Trumpp et al., 1999). This study provided direct evidence that the mandibular process is specified by at least 2 distinct functional regions: 2 large lateral (proximal) regions, where morphogenesis is dependent on and controlled by FGF-8, and a small medial region, in which morphogenesis is independent of FGF-8 and is controlled by other signaling molecules. In these mutants, the symphysial portion of Meckel's cartilage and the mandibular incisors and their associated bones were invariably present. On the other hand, with the exception of the presence of a vestigial malleus, the skeletal elements in the lateral regions of the developing mandible were absent (Trumpp et al., 1999). Molecular analyses indicated that Fgf8;Nes-cre mutants fail to express Lhx6 and, for the most part, Barxl. In addition, although ET-1 expression was not detected in most of the epithelium of the developing mandible, it was detected in the epithelium of the hyomandibular cleft. In these mutants, expression of Gsc was seen only in a restricted region in which cells expressing Barxl and ET-1 were found. These observations indicate that expression of Lhx6, Barxl, Etl, and Gsc in the mandibular arch are dependent, directly or indirectly, on FGF8 signaling. However, expression of Dlxl, Dlx2, Dlx5, and Lhx7 in the mesenchyme of the lateral regions and Pitxl in the mandibular epithelium was unchanged. Although Pax9 was not detected in the molar region of the mutant embryos, it was detected in the regions of presumptive mandibular incisors. The absence of abnormalities in the small medial region and the unaltered patterns of expression of Bmp-4, dHand, eHand, Msxl, and Msx2 (genes that are normally expressed in the medial region) indicate that morphogenesis of the small medial region depends on signals other than FGF8 (Trumpp et al., 1999). The similarities between the phenotypic abnormalities in the Fgf8;Nes-cre mutants and abnormalities in the human first-arch syndromes characterized by agnathia/ micrognathia raise the possibility that mutations in Fgf8 or in
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genes directly upstream or downstream of it might cause some of these human syndromes (Trumpp et al., 1999). Roles for FGFs and FGFRs in craniofacial development are also supported by abnormalities in human syndromes associated with mutations in FGFRs (for reviews, see Muenke and Schell, 1995; Yamaguchi and Rossant, 1995; Webster and Donoghue, 1997; Wilkie, 1997; Naski and Ornitz, 1998). In general, the disorders caused by mutations in FGFRs can be classified into 2 groups: (1) dwarfing conditions and (2) conditions with craniosynostosis. While dwarfing conditions have been shown to be associated with mutations in FGFR3, the second group has been associated with mutations in FGFR2.

expressed in the developing mandible in similar domains in regions near the cells expressing Shh (Platt et al., 1997). The phenotypic abnormalities in Gli2, Gli-3, and
Gli2/Gli3 double-mutants indicated that Gli2 and Gli3 have specific as well as redundant functions in the development of mandibular arch. Both Gli2 and Gli3 mutant mice die at
birth and have severe skeletal and facial abnormalities (Vortkamp et al., 1991, 1992; Hui and Joyner, 1993; Mo et al., 1997). Loss of Gli2 is associated with truncation of the proximal regions of the maxilla and mandible, resulting in the absence of maxillary and mandibular incisors (Mo et al., 1997). On the other hand, Gli3 mutants displayed abnormalities in the maxillary region but not in the mandible (Hui et al., 1994; Mo et al., 1997). In contrast to the single mutant, mandibles of Gli2-/Gli2;Gli3 -/+ mutants were severely shortened and had hypoplastic coronoid, condylar, angular, and alveolar bones. The roles of Shh in craniofacial development have also been elucidated in more recent studies in chick embryos (Helms et al., 1997; Ahlgren and Bronner-Fraser, 1999; Hu and Helms, 1999). Ahlgren and Bronner-Fraser (1999) showed that inhibition of Shh signaling after neural tube closure resulted in a transient decrease in neural tube cell proliferation and an extensive increase in cell death in the neural tube and neural crest. These changes, in turn, resulted in decreased head size and loss of branchial arch structures. The phenotypes observed after reduction of Shh in chick embryos are similar to those observed after cranial neural crest ablation. Mice homozygous for a disruption of Shh die at birth with defects in all tissues, including holoprosencephaly, which is characterized by abnormal forebrain and facial development. Although the branchial arches appear to be normal at E9.5, craniofacial bones are severely affected in Shh null mutants and are almost entirely absent (Chiang et al., 1996). Mice homozygous for the Ptc deletion also die during embryogenesis and have open and overgrown neural tubes (Goodrich et al., 1997). Facial abnormalities in human syndromes associated with mutations in the components of the Hh signaling pathway also support the involvement of the Hh signaling pathway in mandibular and craniofacial morphogenesis (for reviews, see Roessler et al., 1996; Ming and Muenke, 1998; Ming et al., 1998). In humans, haplo-insufficiency of Ptc results in Gorlin syndrome. Partial loss of Gli3 function results in Greig cephalopolysyndactyly syndrome (GCPS), and a point mutation in Shh results in autosomal-dominant holoprosencephaly, one of the most common developmental defects of the forebrain and face.

HEDGEHOG FAMILY
The Hedgehog (Hh) family of secreted proteins is involved in the regulation of a wide range of developmental processes during vertebrate development (for reviews, see Ingham, 1995; Hammerschmidt et al., 1997). There are 3 known mammalian homologs of Hh: sonic hedgehog (Shh), Indian hedgehog (11h), and desert hedgehog (Dhh). Among these, Shh has been shown to be expressed in numerous sites of epithelial-mesenchymal interactions (Bitgood and McMahon, 1995) and is thought to play an important role in many developmental processes, including dorso-ventral patterning of the neural tube and somites, anterio-posterior patterning of the limb buds, morphogenesis of the hindgut, and craniofacial development (reviewed by Bumcrot and McMahon, 1995; BronnerFraser and Fraser, 1997; Weed et al., 1997; Schneider et al., 1999). Most of the details of components of the Hh signaling pathway have been elucidated from studies in Drosophila. A similar signaling cascade is also present in vertebrates (for reviews, see Alcedo and Noll, 1997; Ingham, 1998; Johnson and Scott, 1998; Murone et al., 1999). These studies indicate that Hh signaling is transduced by a heterodimeric receptor complex that includes 2 transmembrane proteins: Smoothened (Smo), a member of the Frizzled (Fz) family of receptors, and Patched (Ptc). Hedgehog proteins bind specifically with high affinity to Ptc without any direct involvement of Smo. However, Smo, which does not directly interact with Shh, is the signaling subunit of the receptor complex. The current model for the Hh signaling pathway suggests that, in the absence of ligand, the Hh receptor complex is inactive, because Ptc interacts with Smo, resulting in repression of Smo signal-transducing activity. Binding of Hh to Ptc causes a conformation change that alleviates this repressive interaction and results in the release and activation of Smo from the complex (Murone et al., 1999). After its activation, Smo activates the transcription of downstream target genes via cubitus interruptus (Ci), a zinc-finger-containing protein, which appears to act as the final component in the Hh signaling pathway (Murone et al., 1999). Homologous to Ci, in vertebrates there are 3 Gli genes: Gli (Glil), Gli2, and Gli3 (for review, see Ingham, 1998). The possible involvement of this pathway in mandibular morphogenesis is suggested by the patterns of expression of genes in the Hh signaling pathway in the developing mouse mandible. Shh is expressed at low levels in the endoderm of the hyomandibular cleft (Platt et al., 1997; Hardcastle et al., 1998). At early stages, Gli2, Gli3, and Smo are expressed throughout the mandibular mesenchyme (Walterhouse et al.,

WNT GENES
The Wnt gene family also constitutes another group of signaling factors with important roles in many developmental processes, including specifications of the dorso-ventral axis of the developing limb (for reviews, see Johnson and Tabin, 1997; Sokol, 1999) and modulation of chondrocyte differentiation in the limb and face (Rudnicki and Brown, 1997; Kawakami et al., 1999). This family consists of at least 15 developmentally regulated genes that encode cysteine-rich glycoproteins (Cadigan and Nusse, 1997; Wodarz and Nusse, 1988). Studies in mice indicate that Wnt5a, -1Qa, -1Ob, and -11 (but not Wnt-1, and Wnt -2) are expressed in the facial mesenchyme (Gavin et al., 1990; Dealy et al., 1993; Parr and McMahon, 1995; Takada et al.., 1994; Tanda et al., 1995; Christiansen et al., 1995; Wang and Shackleford, 1996; Yamaguchi et al., 1999).
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Expression of Wnt5a in the facial processes is best-documented. Wnt5a expression is first detected at the time of formation of the facial processes (Takada et al., 1994; Yamaguchi et al., 1999), and later in a graded fashion (being highest at the tips of the processes) in the frontonasal mass, and in maxillary and mandibular processes (Yamaguchi et al., 1999). The graded pattern of expression of Wnt-5a in the facial processes is similar to its pattern of expression in the developing limb, in which high levels of Wnt5a are expressed in the Apical Ectodermal Ridge (AER) and mesenchymal cells underneath the AER (Dealy et al., 1993; Kawakami et al., 1999; Yamaguchi et al., 1999). These patterns of expression suggest a conserved role for Wnt5a in the morphogenesis of many structures whose development requires extension from the primary body axis (Yamaguchi et al., 1999). This possibility is supported by phenotypes of the homozygous Wnt5a null mutants which have morphological defects in outgrowing tissues, including limb, maxilla, and mandible (Yamaguchi et al., 1999).

ENDOTHELIN PATHWAY
Ligands of the endothelin pathway consist of 3 structurally related small peptide ligands, called ET-1, ET-2, and ET-3, that bind to 2 of the G-protein-coupled endothelin receptors, the endothelin-A receptor (ETA) and the endothelin-B receptor (ETB) (for a recent review, see Kurihara et al., 1999, and references therein). The endothelin pathway also includes 2 isozymes of endothelin-converting enzyme (ECE), ECE-1 and ECE-2 (Kurihara et al., 1999, and references therein). In situ hybridization analysis indicates that the ETA receptor is expressed by migratory CNNC originating from the hindbrain and ECE-1 in the head mesenchyme (reviewed by Kurihara et al., 1999). In the branchial arches, the spatial patterns of ET-1 and ETA expression are complementary, in that ETA is expressed by the CNCC-derived mesenchymal cells of branchial arches and the ET-1 ligand is expressed in the surface epithelium of arches 1, 2, and 3 and in the paraxial mesodermal core of the first branchial arch (Barni et al., 1998; Clouthier et al., 1998, 2000; Kurihara et al., 1999). ECE-1 is expressed in both the mesenchyme and surface epithelium of branchial arches (Yanagisawa et al., 1998). Several components of the endothelin pathway have been inactivated in mice by homologous recombination (Baynash et al., 1994; Hosoda et al., 1994; Kurihara et al., 1994; Clouthier et al., 1998; Yanagisawa et al., 1998). These studies indicate that 2 endothelin-mediated cell-cell signaling pathways (ET-1/ETA and ET-3/ETB) are independently involved in the development of 4 distinct groups of NCC-derived tissues (for review, see Kurihara et al., 1999). Mice deficient in ET-3 and ETB exhibited similar abnormalities and revealed essential roles for ET-3/ETBmediated signaling in the development of epidermal and choroidal melanocytes and enteric neurons (Baynash et al., 1994; Hosoda et al., 1994). On the other hand, mice deficient in ETA and ET-1 showed striking craniofacial and cardiovascular abnormalities that were virtually identical to each other and to those observed in mice deficient for ECE-1 (Kurihara et al., 1994, 1999; Clouthier et al., 1998, 2000; Yanagisawa et al., 1998). In ET-1, ETA, and ECE-1 null mutants, numerous structures derived from branchial arches 1, 2, and 3 were affected (Kurihara et al., 1994, 1999; Clouthier et al., 1998; Yanagisawa et al., 1998). The most striking phenotype in all 3 mutants was the poorly formed mandible that sometimes lacked the midline fusion. The mutant mandibles also exhibited complete absence
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of Meckel's cartilage. The mandibular bone was hypoplastic and highly disorganized, with abnormal articulation to the maxillary arch and the base of the skull. Furthermore, the tongue was severely hypoplastic. Teeth were intact but embedded in loose mesenchyme instead of mandibular bone. The defects observed in ETA-deficient embryos suggest that the mutation disrupts the development of CNCC arising from the posterior midbrain as well as Ri, R2, R4, and R6. This suggests that ET-1 /ETA signaling may be required for cranial NCC migration and/or proliferation (Clouthier et al., 1998; Yanagisawa et al., 1998). While migration of neural crest cells into the arches of ETA-mutant embryos appears unaffected, the absence of ETA signaling appears to affect the proliferation/differentiation of post-migratory crest cells and some apoptosis in the branchial arch mesenchyme. In situ hybridization analysis of E9.5 and E10.5 ETA-/- null mutants indicated either the absence or a significant reduction in the expression of several transcription factors, including Gsc, Dlx2, Dlx3, dHAND, and eHAND in the post-migratory ectomesenchymal cells of the first and second branchial arches. Interestingly, while Barxl expression was absent in the second branchial arch, its expression was unaffected in the first branchial arch of E10.5 ETA-/- embryos (Clouthier et al., 1998, 2000). On the other hand, in these mutants, the expression of other transcription factors-including Prxl, Hoxa2, CRABP1, and Ufdl-was unaffected, suggesting that these factors either act upstream of ETA signaling or belong to different or parallel genetic pathways involved in mandibular development (Clouthier et al., 2000). Analyses of ET1-/- null mutants showed that dHand and eHand are down-regulated in the branchial arches of these mutants (Thomas et al., 1998). The phenotype of ETA null mutant mice resembles the human conditions collectively termed CATCH 22 or velocardiofacial syndrome, and includes severe craniofacial deformities and defects in the cardiovascular outflow tract (Wilson et al., 1993; Clouthier et al., 1998). However, the patterns of expression of Ufdl, a gene shown to be deleted in CATCH 22 patients, was unchanged in ETA-/- null mutants (Clouthier et al., 2000).

NOTCH SIGNALING PATHWAY

The Notch signaling pathway is an evolutionary conserved pathway with essential roles in mammalian embryonic development (for reviews, see Gridley, 1997; Greenwald, 1998; Weinmaster, 1998; Artavanis-Tsakonas et al., 1999). This pathway is characterized by interactions of the receptor Notch with the Delta and Serrate/Jagged families of ligands. Studies in Drosophila showed that the Notch gene encodes large transmembrane receptors that interact with membrane-bound ligands encoded by Delta and Serrate genes (Greenwald, 1998; Artavanis-Tsakonas et al., 1999; Gray et al., 1999). Genes homologous to members of the Notch signaling pathway have been cloned in mammals and include the 4 genes encoding the ligands: Jagged-1 (Serrate-1), Jagged 2 (Serrate 2), Delta-like 1 (Dlll), and Delta-like 3 (D113) (Bettenhausen et al., 1995; Lindsell et al., 1995; Shawber et al., 1996; Dunwoodie et al., 1997; Gray et al., 1999). The importance of the Notch signaling pathway in development is also implicated by the findings that 3 human diseasesT-cell acute lymphoblastic leukemia/lymphoma, the Alagille syndrome, and CADASIL (Cerebral Autosomal Dominant Arteriopathy with subcortical Infarcts and Leukoencephalopathy)-are associated with mutations in genes encoding Notch-1, Jagged-1, and Notch-3, respectively (for reviews, see
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Gridley, 1997; Joutel and Tournier-Lasserve, 1998). Among these, Alagille syndrome exhibits autosomal-dominant inheritance and is one of the major forms of chronic liver disease in childhood (Krantz et al., 1997). Accompanying features of this syndrome include a characteristic facial appearance, including a pointed mandible (Krantz et al., 1997). In the majority of patients, mutations in JAG1 result in the formation of truncated protein, suggesting that Alagille syndrome is due to the haploinsufficiency of JAG1 (Li et al., 1997; Oda et al., 1997; Krantz et al., 1998; Yuan et al., 1998). However, studies in Drosophila support alternative dominant-negative roles for truncated forms of Serrate proteins (Hukriede et al., 1997; Sun and ArtavanisTsakonas, 1997). Studies in developing mice indicate that, whereas Jaggedl (Serratel) is expressed in the maxillary and mandibular mesenchyme, Jagged2 (similar to Notchl) is expressed in the epithelium of the branchial arches (Mitsiadis et al., 1995, 1997, 1998a; Shawber et al., 1996; Sidow et al., 1997; Valsecchi et al., 1997; Jiang et al., 1998). Mice homozygous for Jaggedl null mutations die early in embryogenesis, and mice heterozygous for the Jaggedl null allele exhibit abnormalities in the eye but not in the craniofacial region (Xue et al., 1999). Null mutants of Jagged2 (Jiang et al., 1998) and expression of a hypomorphic allele of Jagged2 (Sidow et al., 1997) exhibit abnormalities in many Jagged2 (Serrate2)-expressing tissues, including defects in the craniofacial region. However, abnormalities in the developing mandible have not been reported.

ed by observations showing that mitogenic growth factors that signal through the Erk-MAP kinases pathway, such as EGF, can antagonize the BMP-induced responses by phosphorylation of Smad-1 at multiple serines in the linker region (Kretzschmar et al., 1997). Although Erk-mediated phosphorylation of Smad-1 does not directly interfere with the association of Smad-1 with Smad-4, it prevents the translocation of Smad-I to the nucleus, thereby inhibiting BMP-4 signal transduction (Kretzschmar et al., 1997; Attisano and Wrana, 1998; Kretzschmar and Massague, 1998). This possibility is supported by the recent observations in micromass cultures (Nonaka et al., 1999) that showed that the addition of EGF inhibited BMP-induced Smadl nuclear translocation and accumulation. The roles of EGF/EGFrs in craniofacial morphogenesis were confirmed by craniofacial abnormalities in Egfr null mutants (Miettinen et al., 1999). The abnormalities in Egfr null mutants included a pointed snout, high incidence of cleft palate, short mandibles, and poorly developed Meckel's cartilage (Miettinen et al., 1999). Furthermore, in Egfr null mutants, there were decreases in the amount of matrix metalloproteinases (MMPs). Inactivation of MMPs in explanted wildtype mandibles resulted in defects similar to those in Egfr null mutants, suggesting that MMPs may act downstream of the

EGF/EGFR signaling pathway (Miettinen et al., 1999).

EPIDERMAL GROWTH FACTOR (EGF)

The EGF-superfamily has been implicated in inductive interactions in the first branchial arch, including those involved in odontogenesis, bone and cartilage formation, and outgrowth of the maxillary and mandibular arches. EGF and EGFR are expressed in the developing mandible (Partanen et al., 1985; Partanen and Thesleff, 1987; Snead et al., 1989; Kronmiller et al., 1991; Shum et al., 1993). Treatment of explants of mouse mandibular arches with EGF antisense oligonucleotides results in the formation of bilaterally symmetrical Fussilli-formed dysmorphic Meckel's cartilage, and inhibition of EGFR kinase activity caused overall retardation in mandibular growth and the complete absence of Meckel's cartilage (Shum et al., 1993). In addition, it has been shown that EGF can substitute for the mitogenic effects of mandibular epithelium on the underlying mesenchyme, suggesting a role for EGF and EGF-like protein in epithelial-mesenchymal interaction involved in the outgrowth of the developing mandible (Coffin-Collins and Hall, 1989; Hall and Coffin-Collins, 1990). A recent study by Nonaka et al. (1999) showed that exogenous EGF inhibited the BMP-4-induced ectopic cartilage in organ-cultured mouse and chick mandibles. It has also been shown that application of EGF-releasing beads to mouse and chick mandibular mesenchyme induces a translucent zone and extensive cell proliferation, and prevents apoptosis (Vaahtokari et al., 1996; Wang et a!., 1998a, 1999). Although EGF beads are not able to induce expression of Msxl, Msx2, and Bmp4 in these mesenchymes, they were able to modulate the effects of BMPs on the expression of Msxl and Msx2 (Wang et al., 1998a, 1999). These observations suggest the possibility that EGF, by modulating the effects of BMPs on the expression of Msxl and Msx2 in mandibular mesenchyme, may be involved in mediating inductive interactions during the initiation phase of odontogenesis and during outgrowth of the mandibular arch (Wang et al., 1999). This possibility is support-

PLATELET-DERIVED GROWTH FACTORS (PDGFs) Mice homozygous for a targeted deletion of the PDGFot receptor that is expressed by CNNC-derived mesenchyme of the branchial arches (Orr-Urterger and Lonai, 1992; Schatteman et al., 1992; Chai et al., 1998) and can bind to all PDGF (for review, see Westermark et al., 1989) exhibit significant defects in the skull, most noticeable in the nasal bone (Soriano, 1997). However, PDGFRot mutants have relatively normal maxillary and mandibular arches (Soriano, 1997). Increased apoptosis observed along the pathway of CNNC migration and mesenchyme of the branchial arches in these mutants suggested
roles for PDGFs and PDGFRo- in the survival of non-neuronal derivatives of CNNC (Soriano, 1997).

MERGING OF THE TWO MANDIBULAR PROCESSES Another essential feature of facial morphogenesis is the union of the facial prominences/processes that occurs either by fusion or by merging of the adjacent processes (for review, see Ten Cate, 1998). In general, the process of fusion seen in the palatal processes involves initial contact and subsequent fusion of the surface epithelia of the neighboring processes, removal of the epithelial cells from the fusion region, and merging of the mesenchymal cells of the neighboring processes (reviewed by Shuler, 1995, and references therein). On the other hand, union of other facial processes, such as the
mandibular processes, appears to involve the merger of 2 incompletely separated processes. During this merger, the furrow between these processes is eliminated (Ten Cate, 1998). The mechanisms for removal of the epithelial cells that results in mesenchymal continuity in facial processes are thought to be mediated by either programmed cell death (apoptosis), epithelial-mesenchymal transformation, or migration to adjacent epithelia (Shuler, 1995). Although in many regions of the developing face, cell death occurs in the epithelium at sites of fusion, analysis of available datas suggest that union of the 2 mandibular processes does not involve epithelial cell death or epithelial-mesenchymal transformation. Rather, it involves
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epithelial cell migration (Shuler et al., 1992; Shuler, 1995; Chai et al., 1997; McGonnell et al., 1998). Studies in the mouse embryo indicate that merger of the 2 mandibular processes starts at E9.5 and is completed within 24 to 36 hrs at Ell (Chai et al., 1997). During this process, the epithelium covering the tips of the mandibular processes consists of 2 cell layers that adhere to each other and subsequently fuse to form an epithelial seam about 3 or 4 cell layers thick. Disappearance of the epithelial seam in the midline is first seen at E10.5 and is completed at Ell, at which time the mesenchymal cells of 2 mandibular processes mix together and become continuous. In contrast to the region of merging in the midline, fusion/merging of the mandibular process to the maxillary process and hyoid process involves epithelial apoptosis (McGonnell et al., 1998). Interestingly, mesenchymal cells around these sites undergo expansion and bi-directional cell movements that result in a mixing of the mesenchymal cells between the 2 mandibular processes and mandibular processes and neighboring processes (McGonnell et al., 1998).

thelial-mesenchymal interactions. Based on patterns of gene expression and on functional studies, the mandibular arch can be divided into 3 overlapping functional regions (Fig. 1A): a small medial region, 2 large lateral regions, and the regions of the hyomandibular clefts located in the lower border of the lateral
regions. Available evidence suggests that each of these regions contains signaling centers. Signaling centers are defined as groups of cells that regulate the behavior of the surrounding cells by producing positive and negative intercellular signaling molecules, including FGFs, BMPs, Hedgehogs, Wnts, and EGFs (Hogan, 1996). The 3 functional regions can be characterized by restricted and region-specific expression of many of the evolutionary conserved signaling factors and transcription factors. During recent years, it has also become clear that the restricted patterns of expression of many regulatory molecules in the mesenchyme of these regions (e.g., Pax9, Barxl, Msxl, Msx2, Gsc) are established by

Conclusions
This review attempts to provide an overview of the current understanding of the putative regions and signaling cascades involved in mandibular outgrowth and morphogenesis. Classic tissue recombination studies have demonstrated that the epithelium is required for outgrowth and correct skeletogenesis in the mandibular arch. However, these studies did not identify specific regions in the epithelium or mesenchyme that regulate the outgrowth of the developing mandible. As was discussed in this review, insight into putative regions and signaling molecules involved in mandibular outgrowth and morphogenesis has come through studies examining: patterns of expression of signaling molecules, functional studies examining the similarities and differences between the effects of signaling molecules and mandibular epithelium, abnormalities in the developing mandible caused by targeted inactivation of candidate molecules, and identification of mutated genes associated with craniofacial abnormalities affecting the mandible in humans. Collectively, these studies show that signaling factors involved in the outgrowth and morphogenesis of the mandibular arch are similar to those involved in morphogenesis of many other organs in which morphogenesis is dependent on epi2001) 12(4) 276-300 (2001) 12(4):276-300

Figure 2. Summary of multiple genetic pathways that are involved in mandibular morphogenesis. The differences in t e signaling cascades in the medial vs. lateral regions of the developing mandible were shown by Trumpp et al. (1 999). Morphogenesis of the large lateral region is dependent on and see Lin et controlled by FGF8. In the lateral region, Fgf8 expression requires Pitx2 [indicated by (1), the and side oral in the expresLhx6 of and Pax9 the and 1 expression et 999b], Lu al., al., 1999; sion of Barxl in both the oral and aboral regions of the hyomandibular cleft is dependent on FGF8 signaling, which also regulates the expression of ET-1 in the mandibular epithelium [indicated by (2), see Trumpp et al., 1999]. In the region of the hyomandibular cleft, the expression of Gsc and Dlx3 is dependent on ET1 /ETA signaling [indicatedby (3) and (A), see Clouthier et al., 1998, 2000]. Gsc expression in this the signaling region is also dependent on DIx5 [indicated by (5), see Depew et al., 1999]. However,factors in this pathway regulating the expression of other signaling molecules and transcription .). by identified (indicated been not fully has region Unlike the lateral region, morphogenesis of the small medial region depends on signals other than FGF8. In this region, the expression of dHand and Msxl is dependent on ET-1 /ETA signaling [indicated by (6), Thomas et al., 1998]. The expression of Msxl and Msx2 in the medial region is [indicated by also de encent on BMP and FGF signaling secreted by the epithelium of medial region in this (7) and (8), see references in the text]. However, the hierarchy of the signaling molecules region and their roles in regulating other genes expressed in the medial region are still not fully understood (indicated by ?).
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stage-specific antagonistic interactions of BMP-4 and FGF-8 signaling in the lateral and medial regions (Neubuser et al., 1997; Thomas et al., 1998; Tucker et al., 1998b). The small medial region (Fig. 1A), where the 2 mandibular processes merge, is characterized by the restricted patterns of expression of Bmp4 in the epithelium and Msxl, Msx2, HAND, Bmp2, and Fgfr2 in the underlying mesenchyme. In addition, Dlx, Prxl, Prx2, and Wnt5a genes are expressed at high levels in the mesenchyme of this region. This region gives rise to the medial region of the mandibular arch containing incisor teeth, the most medially (proximally) located skeletal elements including the symphysis that separates the 2 rods of Meckel's cartilage. Experimental evidence indicates that the medial region is derived exclusively from CNCC originating from the midbrain (Fig. 1B), contains highly proliferative mesenchymal cells that, for the most part, lack in vitro chondrogenic potential, and makes a significant contribution to the overall growth of the developing mandible. Their proliferative activity and the expression of several genes in the mesenchyme of the medial region are dependent on signals derived from the overlying epithelium. The mesenchymal cells in the lower medial region also contain apoptotic cells. Analysis of the available data suggests that epithelial-mesenchymal interactions in the medial region may be involved in directional out-

The medial region may also be involved in inhibiting chonat the midline (symphysis), thus preventing the 2 rods of Meckel's cartilage from fusing and allowing for continued growth and morphogenesis of the mandible and Meckel's cartilage. The abnormalities in Prxl/Prx2 double-knock-outs, and in mice lacking 3 members of the endothelin pathway (ETA, ET-1, ECE-1), suggest essential roles for these genes in the formation of midline structures in the developing mandible. The 2 larger lateral regions (Fig. 1B), where chondrogenesis and osteogenesis are initiated in vivo, are derived from CNNC originating from the midbrain and from R2-4 (Fig. 2A), and give rise to the regions containing the molar teeth, most of the skeletal components of the mandibular arch (including the joint elements), and the middle ear structures. The lateral region is characterized by restricted expression of Fgf8 in the epithelium and high levels of expression of a variety of genes, including Dlx genes, Barxl, Lhx-6/7, Pitxl, Pax genes, and Wnt5a. Knock-outs of many of the genes expressed in the lateral region also result in mandibular hypoplasia of various degrees and/or skeletal abnormalities in the articulating ends of the mandibular arch (coronoid, condylar, and angular processes), indicating that the lateral regions also contain signaling centers regulating mandibular morphogenesis (Fig. 2). The abnormalities in the lateral but not the medial regions of the mandibles of the Fgf8 mutants provide direct evidence that FGF-8 signaling, through interactions with

growth of the developing mandible, and that ET-1/ETA, FGFs/FGFR2C, BMPs/BMPRs, EGF/EGFR, ET-11ETA, and Wnt5a, through their interactions with downstream target genes (including Msx, Prx, and dHand) are a component of the signaling pathway mediating the interactions in this signaling center (Fig. 2). The possible involvement of the medial region in regulating the directional outgrowth of the developing mandible is supported by the expression of mitogens in this region and by abnormalities in mandibular outgrowth in mice lacking regulatory genes that are either specifically expressed in this region (e.g., dHand-/and Msx-1-/-; for more details, see text) or their expression extends into the medial region (e.g., Prxl/Prx2 compound mutants, ET-1-/-, ETA-/-, ETC-1-/-; for more details, see text).

drogenesis

downstream target genes including ET-1, Lhx6, and Barxl, is involved in mediating the interactions that regulate survival, outgrowth, and morphogenesis of this region (Fig. 2). The hyomandibular cleft region separating the mandibular and hyoid arches (Fig. 1A) gives rise to middle ear structures (for review, see Mallo, 1998). In these regions, high levels of expression of many regulatory genes-including Shh, Fgfs, Ffr2c, Ff3, Msxl, Gsc, Prxl, Et-1, Glil, and ptc-are detected in the epithelium and mandibular mesenchyme surrounding these regions (Mallo et al., 1998), suggestive of the intriguing possibility that these additional signaling centers are involved in mandibular as well as middle ear morphogenesis. This possibility is further supported by abnormalities in the developing mandible and middle ear structures of homozygous null mice lacking these genes (Mallo et al., 1998). Furthermore, the mirror-image duplication of caudal mandibular arch skeletal elements in the Hoxa-2 null mutants suggests that inductive signals from the region of the hypomandibular cleft may be involved in the establishment of the polarity of the skeletal elements derived from the caudal region of the mandibular arch, including the middle ear structures (Rijli et al., 1993). Furthermore, branchial arches with normal skeletal polarity develop in embryos in which short segments of the cranial neural tube were rotated along the rostrocaudal axis or dorsoventral axis (Noden, 1978, 1983a,b; Hall, 1982). This suggests the existence of putative signaling centers (polarizing signals) in the local environment into which CNCC migrate and which regulate the polarities of the skeletal tissues within the mandible arch. Although these observations suggest that signal(s) from the hyomandibular cleft may be involved in patterning the skeletal elements within the mandible, the roles of the hyomandibular cleft region in the development of the mandibular arch are poorly understood. Experimental evidence suggests that expression of Gsc in the ectomesenchyme of the hyomandibular cleft region is dependent on FGF8 and ET-1/ETA signaling from the overlying epithelium (Clouthier et al., 1998, 2000; Trumpp et al., 1999) (Fig. 2). These studies also indicate that FGF-8 acts upstream of ET-1 in this pathway (Trumpp et al., 1999). The abnormalities in the mandibular arch in Gsc null mutants are similar to, although less severe than, abnormalities in Dlx5 null mutants, suggesting that these gene products may directly or indirectly interact and function in the same pathway. In situ hybridization studies showed decreased Gsc expression at E10.5 in Dlx5 - null
mutants

(Depew et al., 1999).

The absence of abnormalities in the medial region in FGF8 mutants also provides clear evidence that, unlike the lateral region, the small medial region depends on signals other than FGF8 (Trumpp et al., 1999) (Fig. 2). The similarities in the mandibular phenotypes in dHANDI-, ETA-I-, ETi-l-, Prxl/Prx2 double-knock-outs, and Msxl-/mutants also suggest that direct or indirect interactions between products of these genes are involved in morphogenesis of the medial region. Molecular analyses of dHAND-/-, ETA-!-, ET1-/- mutants indicate that the "ET-1-dHAND-Msxl pathway" constitutes one of the genetic pathways regulating mandibular outgrowth. This pathway suggests that ET-1/ETA signaling is required for high levels of expression of dHAND in the underlying mesenchyme, which, in turn, regulates expression of Msxl (but not Msx2) (Fig. 2). However, the unchanged patterns of expression of Prxl in the mandibles of dHAND-/and ETI-1- mutants (Clouthier et al., 1998, 2000; Thomas et al., 1998) indicate that Prxl is not regulated by ET-1 and either acts
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upstream of dHAND or belongs to different or parallel genetic pathways. Based on the patterns of expression of mRNAs, BMP-4, FGF2, FGF4, and FGF9 are also likely candidates involved in regulating morphogenesis of the medial region. In addition to Bmps, ET-1, and Fgfs, mandibular epithelium also expresses other regulatory genes, including Jagged2, Pitx2, PDGFA, and Egf and Egfr. In situ hybridization analysis shows a lack of Fgf8 in the mandibular epithelium of Pitx2 knock-outs, placing Pitx2 upstream of FGF-8 (Fig. 2). Although the roles of some of these gene products in the outgrowth and morphogenesis of the mandibular arch have been elucidated by phenotypic abnormalities in knock-outs, with few exceptions, the effects of many of these gene products on the expression of the target genes in the mandibular mesenchyme have not been fully examined. In summary, abnormalities in the developing mandibles of various mouse mutants caused by targeted inactivation of individual candidate molecules indicate that multiple factors form a combinatorial code which regulates outgrowth and morphogenesis of the mandibular arch and its skeletal elements. In addition, the similarities between the mandibular phenotypes of various mouse mutants suggest that these gene products regulate mandibular outgrowth (and morphogenesis) through a common pathway by acting on similar populations of cells. These mutants provide powerful tools for examining the hierarchy of signaling molecules involved in mandibular morphogenesis. Furthermore, the generations of compound mutants (mice bearing mutations in different pairs of related genes) provide strong evidence for shared and/or unique functions for these genes and are valuable for placing them within the genetic pathways. Further insight into the roles of these gene products will also come from phenotypic analysis of animals in which candidate genes are overexpressed in the developing mandible. An essential requirement for the performance of these studies in transgenic mice will be the identification of promoter elements, which specifically direct gene expression to the mandibular arch. Furthermore, accessibility of the developing face in the chick embryo for experimental manipulations and infection by means of retrovirus vectors, together with detailed analysis of chick mutants with abnormalities in the lower jaw, will continue to provide invaluable information in the area of craniofacial biology. Elucidating the molecular pathways and mechanisms regulating development and morphogenesis of the mandibular arch is fundamental to an understanding of the pathogenesis of the numerous human congenital syndromes which manifest severe abnormalities of first branchial arch derivatives, including first-arch syndromes, Treacher-Collins syndrome, and Pierre Robin sequence.

anterior neuroectoderm specification during gastrulation.

Acknowledgments
The author thanks Drs. Edward Kollar, William Upholt, Dimitrios Velonis, and Y.-H. Wang, for their helpful discussions and critical comments on the manuscript. The work in the author's laboratory was supported by NIH Grant DE08682

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