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Developmental Biology: Frontiers for Clinical Genetics
Section Editor: Roderick R McInnes e-mail: email@example.com
The molecular regulation of myogenesis
Sabourin LA, Rudnicki MA. The molecular regulation of myogenesis. Clin Genet 2000: 57: 16 – 25. © Munksgaard, 1999 Over the past years, several studies have unraveled important mechanisms by which the four myogenic regulatory factors (MRFs: MyoD, Myf-5, myogenin, and MRF4) control the speciﬁcation and the differentiation of the muscle lineage. Early experiments led to the hypothesis that these factors were redundant and could functionally replace one another. However, recent experiments using in 6i6o and in 6itro models have demonstrated that in fact different aspects of the myogenic program are controlled by different factors in 6i6o, suggesting that these factors play distinct roles during myogenesis. The activity of the MRFs during proliferation and differentiation of muscle precursor cells has clearly been demonstrated to be dependent on speciﬁc cell-cycle control mechanisms as well as distinct interactions with other regulatory molecules, such as the ubiquitously expressed E proteins and several other transcription factors. Furthermore, the observation that the MRFs can recruit chromatin remodeling proteins has shed some light on the mechanisms by which the MRFs activate gene expression. Recently, a functional role for MyoD during satellite cell activation and muscle repair has been identiﬁed in 6i6o, which cannot be substituted for by the other MRFs. This has put forward the hypothesis that these factors also play speciﬁc biological roles following muscle injury and repair.
Luc A Sabourin and Michael A Rudnicki
Institute for Molecular Biology and Biotechnology, MOBIX, McMaster University, Hamilton, Ontario, Canada
Corresponding author: Michael A Rudnicki, McMaster University, 1280 Main St. West, Life Sciences Rm 437, Hamilton, Ontario L8S 4K1, Canada. Tel: + 1 905 5259140 (ext: 27424); e-mail: firstname.lastname@example.org Received 8 October 1999, revised and accepted for publication 14 October 1999
The myogenic regulatory factors (MRFs) are part of a superfamily of basic helix-loop-helix (bHLH) transcription factors including c-myc and acheatescute (1–3). The MRF subfamily consists of MyoD (Myf-3) (4), Myf-5 (5), myogenin (Myf-1) (6), and MRF4 (Myf-6/Herculin) (7 – 9). Twelve years ago, the MyoD gene was ﬁrst isolated from subtractive hybridization procedures using myoblast-speciﬁc cDNA libraries (4). The MyoD cDNA was identiﬁed by virtue of its ability to convert ﬁbroblasts into myogenic cells. Subsequently, low stringency library screens uncovered three more MRFs all capable of inducing myogenic conversion when overexpressed in a vast number of nonmuscle cell lines. The MRF proteins contain a conserved basic DNA-binding domain essential for sequence-speciﬁc DNA binding and a helix-loop-helix motif required for heterodimerization. Each of the MRFs has been shown to heterodimerize in 6itro and in 6i6o with E proteins and to bind DNA in a sequence-speciﬁc manner at sites known as E-boxes (CANNTG). This DNA motif
is present in the promoters of many skeletal muscle-speciﬁc genes and mediates gene activation in an MRF-dependent manner (1–3, 10–12).
Expression of the myogenic factors during embryogenesis
The genes encoding the four MRFs have been shown to be expressed in a temporally distinct pattern. As determined by in situ hybridization, activation of Myf-5 occurs ﬁrst in the rostral somites of the mouse around 8 days postcoitum (dpc) and is down-regulated after day 14 (13). The activation of myogenin is observed at 8.5 dpc followed by MyoD at about 10.5 dpc along with markers of terminal differentiation (14). MRF4 is expressed transiently between days 9 and 12 and repressed until after birth (15). In the limb bud, Myf-5 is expressed transiently between days 10 and 12, followed by co-expression of myogenin and MyoD after day 10.5 and MRF4 after day 16 (13–15). The speciﬁc promoter elements that gov-
A ﬁrst element. Myf-5-deﬁcient mice display normal skeletal muscles but die perinatally because of severe rib defects (31). appear to be required for myogenic determination. In addition. whereas the secondary MRFs. normal migration of Pax-3-expressing cells into the limb buds and subsequent induction of Myf-5 in myogenic precursors are observed. In contrast. The primary MRFs. inactivation of MRF4 results in viable mice with apparently normal muscles but with a fourfold increase in myogenin expression (37–39). MyoD-/. found 20 kb upstream of the MyoD start site. demethylation of the MyoD locus has been demonstrated to play an important role during its activation de no6o (25). 23). Further dissection of the MyoD promoter will likely uncover other enhancer elements important for the MyoD gene activation. The control of MyoD expression through the − 20-kb element appears to be E-box-independent (24). In an independent study. The committed cells (myoblasts) can proliferate and further differentiate into myocytes and mature into myoﬁbers under the action of the secondary MRFs. overexpression of Pax-3 in cultured myoblasts inhibits terminal differentiation in 6itro and this phenomenon appears to be dependent on Pax-3 DNA-binding activity (29). 1). suggesting that Myf-5 expression in the limb is insufﬁcient for the normal progression of myogenic development (41). Recently. suggesting the existence of potential redundancy among the MRFs (40). Gene targeting experiments have provided much insight into the functions of the MRFs in 6i6o. However. introduction of the myogenin cDNA into the Myf-5 locus is able to rescue the rib Fig. located 5 kb upstream of the core promoter region. the use of MyoD-lacZ transgenic mice bred into the MyoD. demonstrating that MyoD acts downstream of these genes during myogenesis (26) (and reviewed in (27)). are required downstream of MyoD and Myf-5 as differentiation factors (Fig. Tajbakhsh and co-workers have shown that expression of MyoD is dependent on either Myf-5 or Pax-3 (a paired-box domain protein). Mice lacking myogenin display a normal number of myoblasts but die at birth because of an absence of myoﬁbers (35. myogenin and MRF4.embryos exhibit normal muscle development in the limb buds and branchial arches. In contrast. Furthermore.mice display normal epaxial (paraspinal and intercostal) muscle development. 36). In addition. and markedly delayed development of epaxial muscles (41). Taken together. The introduction of null mutations in the four MRFs into the germline of mice has demonstrated the existence of a hierarchical relationship among the MRFs. 33). Targeted inactivation of the MRFs has deﬁned two groups of factors. Interestingly. ectopic expression of the Pax-3 gene in embryonic tissues was shown to induce the expression of MyoD and Myf-5 (28). Interestingly. MyoD and Myf-5.The molecular regulation of myogenesis ern the temporo-spatial expression of the MRFs have yet to be fully deﬁned. 22). Targeted inactivation of the MRF genes defect and results in viable and fertile mice but is unable to fully compensate for the absence of Myf-5 during myogenic determination (32. these experiments have then deﬁned two groups of MRFs. suggesting that its expression is MRFdependent. These observations suggest that MyoD and Myf-5 play distinct roles during the formation of epaxial and hypaxial muscles and argue against the existence of redundancy among the MRFs. whereas hypaxial (limb and abdominal wall) development is delayed by 2. Induction of the myogenin gene has been shown to be dependent on an E-box and a myocyte enhancer factor-2 element for proper expression in the somites and limbs of the developing mouse. Similarly. several studies have identiﬁed speciﬁc enhancer elements for MyoD and myogenin (16 – 23). in part (17. myogenin and MRF4. are required at the determination step for commitment of the proliferating somitic cells to the myogenic lineage. has been demonstrated to direct the expression of a LacZ reporter gene during embryogenesis in speciﬁc somitic subdomains (19 – 21). The primary MRFs. In contrast. The superposition of the expression patterns generated by both enhancers results in a pattern that is indistinguishable from the endogenous MyoD gene. MyoD and Myf-5. 1. A second enhancer. these studies have demonstrated that some MRFs can substitute for one another without affecting overall muscle development. Inactivation of MyoD in mice results in an apparently normal muscle phenotype with a fourfold increase in Myf-5 expression (30).5 days (Fig. The expression of the MyoD gene during embryogenesis has been found to be regulated by at least two distinct enhancers. mice deﬁcient for both MyoD and Myf-5 die at birth owing to a complete absence of skeletal myoblasts and muscle (34). directs MyoD expression during the terminal differentiation of myogenic precursor cells into myotubes and myoﬁbers (18. Myf-5-/. However. 2). 17 .or Myf-5-deﬁcient backgrounds has been used to address potential redundancy (41).
suggesting a speciﬁc role for Myf-5 in the establishment of the epaxial musculature. 46). MyoD has recently been shown to be negatively regulated by dimerization with Mist1. The p21 gene has been demonstrated to bear E-box in its upstream regulatory regions and is activated by MyoD overexpression in transient assays (53). For example. Regulatory mechanisms of MRF activity In 6itro differentiation systems have provided further into the regulation of MRFs activity and the relationships between growth and differentiation. Various other oncogenes such as c-myc. encoded by at least four different genes (Id1. expressed in differentiated myocytes.5 days. The temporal expression pattern of a MyoD-LacZ transgene in different null background shows that the –5-kb enhancer of MyoD. directly binds MyoD and inhibits its activity (59. 57).Sabourin and Rudnicki Fig. Myf-5-/.embryos exhibit normal muscle development in the limb buds and branchial arches. In addition to Id and mTwist proteins. The activity of the MRFs is further coupled to cellular proliferation by the negative regulatory effect of the AP1 heterodimer Fos/c-Jun. 3 and reviewed in (2)). a novel bHLH factor that lacks a transactivation domain (48). MyoD activity has been shown to be inhibited in 6itro by the murine twist (mTwist) protein (47). The activity of the MRFs is also tightly coupled to the cell cycle (reviewed in (49. it is not clear whether speciﬁc heterodimers play distinct biological roles. 3). high expression of p21 has been correlated with the activation of the myogenin gene during embryogenesis (55). c-Jun. These heterodimers activate muscle-speciﬁc transcription of E-box-containing muscle gene promoters (44). a G1-S cyclin and a Cdk4 activator. The mTwist protein is also thought to sequester E proteins. suggesting . The resulting heterodimer does not bind E-box-containing promoters. 60). MyoD-/. act in a dominant negative manner by heterodimerizing with E proteins preventing their association with the MRFs and subsequent muscle-speciﬁc gene activation (46) (Fig. Cip1) and p16 (52–54). Furthermore. Id2. preventing MRF-E protein heterodimer formation. Myogenic cell lineages. N-ras. Id3. The MRFs have been shown to be negatively regulated by the HLH protein Id. which lacks a basic DNA-binding domain (45. 50)). In contrast. The Id factors. and ITF1) (42–44) (see Fig. The Rb protein is also necessary to maintain the differentiated phenotype of cultured myotubes. The proto-oncogene. 3). inhibits MyoD activity and subsequent transactivation of E-boxcontaining reporter genes (56. Similarly. and Ha-ras also inhibit muscle differentiation in 6itro. the hypophosphorylated form of the retinoblastoma protein (Rb) has been demon18 strated to associate with MyoD and to be required for efﬁcient transactivation of E-box-containing muscle-speciﬁc promoters (51). The cell-cycle MRF connection is further substantiated by the observation that overexpression of cyclin D1. upon differentiation of cultured myoblasts in 6itro. In addition. Several studies have demonstrated that the MRFs can efﬁciently heterodimerize with products of the E2-2 (ITF2) and E2-5 genes (E12. demonstrating a functional role for MyoD in the establishment of the hypaxial musculature. This interaction appears to require the cyclin D1-dependent nuclear targeting of Cdk4. E47. Supporting these observations.mice display normal epaxial muscle development. and Id4). whereas hypaxial development is delayed by 2. the c-Fos promoter is down-regulated by MyoD through an E-box within the c-Fos promoter (61). Furthermore. and markedly delayed development of epaxial muscles. is activated in the epaxial lineage (blue) in the absence of MyoD and in the hypaxial domain (red) in the absence of Myf-5. 2. However. induction of differentiation in cultured myoblasts results in up-regulation of the cell-cycle inhibitors p21 (WAF-1. MyoD activity has been demonstrated to be downregulated by direct interaction with the C-terminal domain of Cdk4 (58) (Fig.
through p300/CBP. The activity of the MyoD family is coupled to cell-cycle control.(IGF-1) or FGF-2-induced myogenesis (73). the mitogen-activated protein kinase (MAPK) pathway has been shown to be activated in differentiating muscle cells and to positively regulate the expression and activity of the MyoD protein (71). whereas blunt red arrows denote negative regulatory relationships. activated cyclin-dependent kinases (Cdk4) inhibit MyoD activity through direct interaction. or are transcription factors themselves. This interaction was demonstrated both in 6i6o and in 6itro and appeared to be required for the terminal differentiation of cultured myoblasts. in contrast. RNA polymerase II functions. Recently. MyoD interacts with the histone acetyltransferase PCAF in a multiprotein complex also containing p300/CBP (78). protein kinase A negatively regulates myogenin through an indirect mechanism (70). 19 . MRF activity is also potentially negatively regulated through phosphorylation. In addition. withdrawal from the cell cycle is maintained by a positive feedback loop in which high p21 and Rb expression prevents re-entry into the cell cycle and the MRF-E protein complex is activated. Upon differentiation. upstream of the basic DNA- Fig. Similarly. 78). is detrimental to insulin-like growth factor-1. the activity of stress-activated protein kinase 2 (SAPK2/p38) has also been demonstrated to be important for the terminal differentiation of C2C12 myoblasts (74). This interaction occurs through the carboxyl cysteine/histidine-rich (C/H3) domain of p300 and increases the ability of MyoD to transactivate an E-box-containing reporter construct (76. Supporting this. Similarly. 3. continuous activation of MEK. a MAP kinase kinase. myogenin is phosphorylated directly by protein kinase C (PKC) in 6itro and in 6i6o (69). Active gene expression is associated with histone acetylation and loss of histone/DNA interaction. Fibroblast growth factor (FGF) treatment or PKC overexpression results in threonine-87 phosphorylation in the DNA-binding domain and a loss of DNA-binding activity. However. Among the co-activators. Whether different components of the MAPK pathway play distinct biological roles during growth or differentiation remains to be elucidated. Interestingly. 68). Green arrows denote positive. Recently. attempts at identifying the mechanisms underlying MRF functions have uncovered a number of MRF-binding proteins and co-factors.The molecular regulation of myogenesis that growth-promoting factors negatively regulate the MRFs (62–66). in addition to p300/CBP. is crucial for activation of the myogenic program. these co-activators are known to play important roles in chromatin remodeling. Interestingly. MyoD has been shown to interact directly with p300/CBP (75–78). In a separate study. Gerber and co-workers have demonstrated that a cysteine-histidine-rich region of MyoD. Regulation of transcription through MRF/co-factor interactions In recent years. Disruption of this complex by anti-PCAF antibody microinjection inhibits muscle differentiation. viral oncogenes such as adenovirus E1a inhibit differentiation and MRF activity by direct physical interaction (67. In proliferating myoblasts. For example. indicating that recruitment of histone acetyltransferase activity of PCAF by MyoD. Bennet and co-workers have demonstrated that upon mitogen withdrawal from C2C12 myoblasts. the MAPK p42Erk2 is inactivated concomitant with up-regulation of muscle-speciﬁc genes (72). they showed that overexpression of MAPK phosphatase-1 inhibited p42Erk2 activity and was sufﬁcient to relieve the inhibitory effects of mitogens on muscle-speciﬁc gene expression. Expression of Id proteins precludes the formation of E protein-MRFs heterodimers.
called myogenic precursor cells (mpcs). suggesting that self-renewal in the satellite cell compartment maintains a population of quiescent cells (89). MyoD also interacts with components of the transcriptional machinery. including injury (89 – 91). Satellite cells are normally mitotically quiescent but are activated and re-enter the cell cycle in response to stress induced by weight-bearing exercise or trauma. muscle hypertrophy. is necessary for chromatin remodeling and gene activation by MyoD (79). However. Transcription factors such as MEF2-C. Satellite cells arise around 17 dpc during mouse embryogenesis and are believed to represent a unique myoblast lineage. Similarly.mice (30) with mdx mice. for which overexpression has been shown to inhibit myoblast differentiation (81). making it . and thus is an animal model for human Duchenne and Becker muscular dystrophy (93). quiescent satellite cells display no detectable levels of either of the four MRFs (96). the de no6o induction of Myf-5 and MyoD transcription implies that inductive signals are involved. the molecular mechanisms underlying the activation and function of myogenic stem cells are still unclear. The total number of quiescent satellite cells in adult muscle remains relatively constant over multiple cycles of degeneration and regeneration. In addition. MyoD is rapidly up-regulated within 12 h. such as Duchenne muscular dystrophy (DMD). a marker for cell proliferation. The absence of MRF mRNA in satellite cells prior to activation suggests that satellite cells represent a stem cell lineage that is distinct from myoblasts. Recently. Muscle regeneration and satellite cell function: role of MyoD Satellite cells. In addition to these factors. Such genetic modiﬁcations include the ampliﬁcation of MDM2. undergo multiple rounds of division prior to fusion with the existing 20 or new myoﬁbers. a member of the MEF2 family of transcription factors. Subsequently. 92). has been shown to bind and enhance the activity of MRFs-E12 heterodimers (88). reside beneath the basal lamina of adult skeletal muscle closely juxtaposed against the muscle ﬁbers (89). heterokaryon formation studies have revealed that rhabdomyosarcomas are deﬁcient for an unknown factor required for MyoD activity (82). a MEF2-related protein. Furthermore. there is evidence that mutations in co-factors for the MRFs are contributing to the pathogenesis of rhabdomyosarcomas. the TATA-binding protein TFIID has been identiﬁed as a novel MyoD-binding protein and found to stabilize the binding of MyoD to its consensus binding site (83). which is likely due to high levels of ongoing regeneration (93. Satellite cells appear to form a population of stem cells that are biologically and biochemically distinct from their descendant mpcs (89. The mdx mice display a high regenerative capacity leading to muscle hypertrophy. Following proliferation. and postnatal muscle growth has been demonstrated extensively (89. Although no known muscle diseases have been associated with genetic alterations in any of the MRFs (80). both factors are co-expressed during the proliferative phase. The essential role played by satellite cells in muscle regeneration. the numbers and proliferative potential of satellite cells become progressively reduced in muscle diseases presenting with muscular atrophy. Satellite cells make up 2–7% of the nuclei associated with a particular myoﬁber. The expression of myogenin occurs last during the time associated with fusion and differentiation (97. myogenin and MRF4 are expressed in cells entering the terminal differentiation program. analogous to those that occur during embryogenesis (27. The mdx mouse carries a loss of function point mutation in the X-linked dystrophin gene.Sabourin and Rudnicki binding domain. The daughter cells of the activated satellite cells. 98). serum response factor. MyoD has been observed to facilitate the association of TFIIB with the preinitiation complex subsequent to DNA binding. has also been demonstrated to interact directly and synergize with the MyoD-E12 heterodimer but not with either protein alone (reviewed in (85–87)). the stem cells of adult skeletal muscles. This proportion varies with age and a particular muscle group. Analysis of gene expression by reverse transcription-polymerase chain reaction of individual satellite cells following their activation in intact muscle ﬁbers (96) substantiates that quiescent satellite cells express no detectable MRFs but do express the c-met receptor tyrosine kinase (the receptor for hepatocyte growth factor). The role of MyoD in satellite cell function has been investigated by interbreeding MyoD-/. 92. 94). This up-regulation of MyoD occurs prior to the expression of proliferating cell nuclear antigen (PCNA). Activated satellite cells ﬁrst express either Myf-5 or MyoD. Upon injury and activation. Furthermore. 99). 95). As determined by polymerase chain reaction analysis. However. Satellite cells mediate the postnatal growth of muscle and contribute for the most part to the formation of the adult muscle mass (89). Interaction of the MRF-E12 dimers with muscle LIM protein also results in increased DNA-binding activity and stimulation of myogenesis (84).
myogenic cells and a requirement for M-cadherin has been reported for cell-cycle withdrawal and myoblast fusion (106. 4). suggesting that overexpression Fig. whereas MyoD-/. Future work It is now well established that the MRFs constitute a group of four bHLH transcription factors that play a pivotal role during the speciﬁcation and differentiation of muscle cells. Taken together. the expression of differentiation-speciﬁc markers is drastically reduced or absent in MyoD-/cells. In the absence of MyoD.cells has demonstrated that the MyoD-/. Furthermore. it will be of interest to identify additional regulatory components such as kinases.hind limb muscle were generated and analyzed for proliferative and differentiation potential. One possibility is that IGF1 promotes proliferation and inhibits differentiation of MyoD-/.muscle tissue.myogenic cells exhibit a ﬁbroblast-like morphology distinct from the bipolar morphology of wildtype myoblasts (102). 107). These data suggest that up-regulation of MyoD is required for satellite cells to enter the mpc proliferative phase prior to terminal differentiation. mdx :MyoD-/. Since Myf-5-/.muscle and 13-fold in mdx :MyoD-/. Upon activation. but do not express desmin. Studies have shown that the compound mutant mice (mdx :MyoD-/-) exhibit markedly increased penetrance of the mdx phenotype characterized by muscle atrophy and increased myopathy leading to premature death (100). In addition. culture mixing experiments using LacZ -marked MyoD-/.mice and is characterized by an almost complete absence of proliferative myogenic precursor cells as determined by 3H-thymidine incorporation or immunohistochemistry with antibody reactive to PCNA (100).cells continue to proliferate and yield reduced numbers of predominantly mononuclear myocytes after several days in differentiation medium (102. the expression of M-cadherin is markedly reduced in MyoD-/. several signaling pathways that regulate MRF activity have been identiﬁed. a deﬁnitive role for Myf-5 in satellite cell activation has yet to be determined. In the absence of MyoD. Myogenic cells lacking MyoD express c-met (96. Interestingly. quiescent satellite cells. electron microscopic examination of MyoD-deﬁcient muscle reveals the presence of morphologically normal satellite cells.cellular phenotype is cell autonomous. However. 4.myoblast cultures display a fourfold increase in Myf-5 mRNA expression. Muscle regeneration is severely impaired in MyoD-/. 105).muscle. Role of MyoD in satellite cell function. expression of IGF -1 is markedly increased in MyoD -/. expressing c-met.muscle. wildtype myoblasts undergo cell-cycle arrest and fuse into multinucleated myotubes. mdx:MyoD -/.The molecular regulation of myogenesis an attractive model to investigate the role of the MRFs during muscle regeneration. To gain insight into the regeneration deﬁcit of MyoD-/.mice die perinatally (31). In addition. 103).8-fold in MyoD-/.myogenic cells cultured under differentiation conditions. cell counts show that their relative abundance is increased by 1. Following the induction of differentiation in 6itro. these results suggest that MyoD-/myogenic cells represent an intermediate stage in the satellite cell activation pathway downstream of the quiescent state but upstream of the mpc compartment (102) (see Fig. However.myoblasts via an autocrine loop. Expression of Myf-5 alone may allow self-renewal either before returning to quiescence (yellow arrow) or up-regulating MyoD and formation of proliferative mpcs (white arrows). these experiments strongly support the hypothesis that satellite cells form a stem cell compartment that is the source of myogenic precursor cells (100).animals also display severe cardiomyopathy. and other transducers that are directly controlling the activity of the MRFs under growth and differentiation condi21 . However. By 3 – 5 months of age. of Myf-5 cannot alleviate the differentiation defect imparted by the inactivation of MyoD in these cells. ﬁrst express Myf-5 or MyoD before co-expressing both and progressing through the developmental program. To date. a hallmark of DMD patients (101). Interestingly. phosphatases.mice develop a profound dorsal– ventral curvature of the spine similar to the lordosis and kyphosis of patients with DMD. unlike mdx mice. an intermediate ﬁlament protein typically expressed in myoblasts in 6itro and in 6i6o (104). suggesting that MyoD normally negatively regulates IGF-1 expression in primary myogenic cells. Taken together. As for MyoD-/. Low passage MyoD-/. myogenic stem cells undergo several rounds of division and return to a quiescent state rather than progressing through the developmental program. MyoD-/. satellite cell-derived primary cultures from adult MyoD-/. satellite cells appear to exhibit a propensity for self-renewal rather than progression through the differentiation program.
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