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LIN-12/Notch signaling in C.

Iva Greenwald§, Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, Columbia University, College of Physicians and Surgeons, New York, New York 10032 USA

Table of Contents
1. Introduction ............................................................................................................................ 2 2. Genetic identification and characterization of LIN-12 and GLP-1 ...................................................... 2 3. Overview of signal transduction by LIN-12 and GLP-1 ................................................................... 3 4. Identification and characterization of core components ................................................................... 4 4.1. Ligands ....................................................................................................................... 4 4.2. Site 2 (extracellular) cleavage .......................................................................................... 5 4.3. Site 3 (transmembrane) cleavage ...................................................................................... 5 4.4. The nuclear complex ...................................................................................................... 7 5. Identification of modulators of lin-12 and glp-1 activity .................................................................. 7 5.1. Suppressors of lin-12(d) ................................................................................................. 7 5.2. Suppressors of a lin-12 hypomorph ................................................................................... 8 5.3. Suppressors of glp-1 hypomorph ...................................................................................... 8 5.4. Enhancers of a glp-1 hypomorph ...................................................................................... 8 5.5. Enhancers of glp-1 gain-of-function .................................................................................. 9 5.6. Suppressors of Presenilin ................................................................................................ 9 6. Lateral specification and induction mediated by LIN-12 and GLP-1 .................................................. 9 7. Future prospects .................................................................................................................... 10 8. Acknowledgements ................................................................................................................ 10 9. References ............................................................................................................................ 10 Abstract Receptors of the LIN-12/Notch family mediate cell-cell interactions during animal development, and aberrations in LIN-12/Notch signaling have been implicated in human disease. Studies in C. elegans have been instrumental in defining the basic features of the LIN-12/Notch pathway, the role of LIN-12/Notch proteins as receptors for intercellular signals, the mechanism of signal transduction, and the regulation of LIN-12/Notch signaling during cell fate decisions. This chapter is focused on detailing how the "awesome power of C. elegans genetics" has identified many core components and modulators of LIN-12/Notch activity.


Edited by Lisa R. Girard. Last revised July 29, 2005. Published August 8, 2005. This chapter should be cited as: Greenwald, I. LIN-12/Notch signaling in C. elegans (August 4, 2005), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.10.1, Copyright: © 2005 Iva Greenwald. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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. dominant alleles of glp-1 that cause the opposite phenotype--continued mitotic proliferation of the germline at the expense of gamete production--were identified (Berry et al. and intragenic reversion yielded null alleles. encompassing signals and receptors as well as DNA binding proteins. Greenwald et al. elegans has two LIN-12/Notch proteins.. see also Notch signaling in the C. including early gonadogenesis. Hutter and Schnabel. 1989.1983. The requirement for lin-12 activity for appropriate cell movements that result in a left-right intestinal twist may also be considered as a role in cell function. Possible roles for lin-12 activity in differentiation or function. elegans 1. anus and excretory cell. Subsequent experiments revealed another role for glp-1 maternal activity in mediating a critical inductive event at the 4-cell stage of embryogenesis (Mango et al. elegans embryo). between otherwise identical cells (Hermann et al. 1995). The focus of this review will be on the contributions of genetic analysis of LIN-12/Notch signaling in C. the discovery that LIN-12/Notch proteins in C. McGinnis et al. as well as a duplication of the excretory pore. Newman et al. A screen for maternal-effect embryonic lethal mutations revealed that loss of maternal glp-1 activity prevents induction of the anterior pharynx at the 12-cell stage of embryogenesis (Priess et al. encoded by the lin-12 and glp-1 genes. Genetic identification and characterization of LIN-12 and GLP-1 C.. as GLP-1 can substitute for LIN-12 in cell fate decisions (Fitzgerald et al. 2005). 1984). 1994). Hansson et al. 1991. systematic analysis in worms and flies has illuminated how LIN-12/Notch proteins transduce signals. These genes were identified through genetic screens for developmental mutants. Double mutants lacking both lin-12 and glp-1 activity revealed that the two genes are functionally redundant in some cell fate decisions (Lambie and Kimble.1985). A screen for sterile mutants revealed that loss of 'zygotic' glp-1 activity limits germline proliferation and causes germ cells to enter meiosis prematurely (Austin and Kimble. and contexts in which this signaling system is used and modulated. glp-1 was identified in two different. as opposed to cell fate specification per se. as well as the Lag phenotype of the lin-12 glp-1 double mutant. were dominant and hypermorphic.. Harper et al. Introduction Coming soon after the finding of a conserved 'homeobox' in developmental control genes (Laughon and Scott. 2 . lin-12 was identified in a genetic screen for mutations that have defective vulval development (Greenwald et al. 2000). elegans embryo). so it is not surprising that some functions have been conserved... Ferguson and Horvitz. rather than cell fate. Rudel and Kimble. 1983).. reflecting defects in cell fate decisions that occur during embryogenesis (Lambie and Kimble.. 2003. and sex mesoblast specification (see Male development.. Subsequently. lin-12 also is required for π cell specification during hermaphrodite gonadogenesis (see Hermaphrodite cell-fate specification. 1987). and genetic analysis has established both unique and redundant roles for the two genes in specifying cell fates. The functional redundancy inferred from genetic analysis is due to biochemical redundancy of the two receptors. Moskowitz et al. 2003). Mello et al. and at least four other interactions in the early embryo (see also Notch signaling in the C. elegans and Drosophila contain epidermal growth factor (EGF)-like repeats (Greenwald. Phenotypic analysis indicated that lin-12(d) and lin-12(0) alleles cause opposite transformations in many different cell fate decisions. As described below..LIN-12/Notch signaling in C. 2002).. The hallmarks of the Lag phenotype are the absence of a rectum.. 1991). genetic screens for other components of the LIN-12 and GLP-1 signaling pathways have exploited the highly penetrant phenotypic defects of single mutants in screens for extragenic suppressors and enhancers. Wharton et al. New roles for LIN-12/Notch signaling in mammalian development and disease have been identified at a prodigious rate (Gridley. 1993).. Chao et al. called lin-12(0) (Greenwald et al. 1983). contemporaneous genetic screens.. 1994.. 1987). 2002. The first alleles discovered... and also that basic signaling systems would be conserved. for "Lin-12 and Glp-1". 1994.. 1986) suggested that the kinds of molecules that underlie common developmental mechanisms shared by all animals would be very broad. lin-12 and glp-1 appear to have arisen by gene duplication (Yochem and Greenwald. called lin-12(d) alleles. 2003. 2004). The distinctive phenotype of the lin-12 glp-1 double is called Lag. vulval precursor cell fate specification (see Vulval development). In subsequent years. 1994. 1985.. have also been described (Eimer et al. 1984. Pepper et al. elegans has made to illuminating universal aspects of this essential conserved pathway. Kidd et al. 2. 1985. 1997.

SWI6. as represented by the single cartoon. elegans LIN-12/Notch proteins. followed by three copies of the LIN-12/Notch repeat (LNR) motif. Conserved motifs: EGF = epidermal growth factor-like motif. 1993). followed by one or more EGF motifs. the "DSL motif". Schroeter et al. Ligands for LIN-12 and GLP-1 (Figure 1) are members of the "DSL" family. both have the same arrangement of motifs. LIN-12 and GLP-1. Overview of signal transduction by LIN-12 and GLP-1 LIN-12 and GLP-1 have all of the hallmarks that define the LIN-12/Notch family (Yochem and Greenwald. 2000. Serrate) and C.. an acronym derived from canonical ligands from Drosophila (Delta. releasing the intracellular domain. but Western blots of GLP-1 are consistent with this possibility (Crittenden et al.. Struhl and Adachi. The remaining transmembrane protein.LIN-12/Notch signaling in C. and Ankyrin. elegans proteins are also cleaved by furin. and a canonical PEST protein turnover motif. Figure 1). is cleaved constitutively within the transmembrane domain at "site 3" (Figure 1 and Figure 2). Inferred cleavage sites are shown (see also Figure 2). representative transmembrane and secreted DSL proteins are shown. which translocates to the nucleus (Kopan and Goate. 3 . 1998. 2000. 2000. Struhl et al.. 1998. There are two C. elegans (LAG-2). elegans 3. LNR = LIN-12/Notch repeat motif. Figure 1. Figure 1). Schematic representation of C. These ligands also contain one or more EGF motifs. elegans LIN-12/Notch and DSL proteins. 1994). The intracellular domain of LIN-12/Notch proteins contains repeated "CDC10/Ankyrin" motifs. There are ten predicted DSL proteins. A spacer region between the LNR motifs and the transmembrane domain contains two conserved cysteines. They are type I transmembrane proteins that contain multiple EGF-like motifs commencing just after the signal sequence. Binding of DSL ligands to LIN-12/Notch leads to shedding of the LIN-12/Notch ectodomain via cleavage at "site 2" within the spacer region of the extracellular domain (Figure 1 and Figure 2). it is not known whether the C. CDC10/Ank = a motif found in yeast CDC10. 1989. Yochem et al. All ten DSL proteins have a single amino-terminal DSL domain.. Struhl and Adachi. with only a short extracellular stub. Vertebrate LIN-12/Notch proteins are cleaved by furin in this spacer region during their transit through the secretory system at "site 1" (Brou et al. as well as an amino terminal motif that is unique to the family. 1988..

. The intracellular domain contains a block of repeated CDC10/SWI6/Ankyrin motifs. Hsieh et al. thereby turning on the expression of target genes (Jarriault et al. LAG-1 is a member of the "CSL" family. 1996. 1991). lag-2. See text for further description. Identification and characterization of core components Given the mechanism of signal transduction. 1994).. Then. was recovered in two different genetic screens: null alleles of lag-2 were identified based on the Lag phenotype they confer (Lambie and Kimble. 2004b). and alternate models to explain these observations did not fall out of favor until compelling in vivo analysis in Drosophila (Struhl and Adachi. it became clear that there are a total of ten genes that encode members of the DSL ligand family (Chen and Greenwald. elegans. along with the juxtamembrane region. elegans Figure 2. which. elegans ligand. the intracellular domain could not be visualized in the nucleus under normal circumstances. and briefly summarize the state of understanding about these components from work in C. Tax et al. an acronym derived from mammalian CBF1 and Drosophila Su(H) as well as LAG-1. Molecular cloning and sequence analysis revealed that lag-2 encodes a protein homologous to the known Drosophila Notch ligands Delta and Serrate (Henderson et al. was identified in a genetic screen for maternal-effect lethal mutants (Mango et al. Studies of Su(H) and CBF1 suggest that the intracellular domain of LIN-12/Notch proteins convert CSL proteins from repressors into activators. With the completion of the genomic sequence. 1994. I will detail how the core components were identified and characterized in C. 1994. 4. This mechanism of signal transduction was first suggested when expression of the intracellular domains of LIN-12 in C. In this section. and unusual antimorphic alleles were identified as dominant suppressors of the egg-laying defect caused by a lin-12(d) mutation (see below. apx-1. 1994. Ligands The first identified C. elegans ligand. 4. the core components of the pathway may be considered to be proteins that are directly involved in liberating the intracellular domain from its membrane tether.. The core components and their Drosophila and mammalian counterparts are summarized in Table 1.. One of 4 .. However. mediate the physical interaction with the sequence specific DNA binding protein LAG-1 (Christensen et al. 1994).1993). 1998) and biochemical analysis in mammalian cells (Schroeter et al. 1997). 1996). Mello et al. 1995. with accumulation of the intracellular domain of Notch observed in the nucleus (Struhl et al. elegans and Notch in Drosophila caused constitutive activation.. it was found that the CSL DNA binding protein mediated transcription of Notch target genes and associated physically with the intracellular domain of Notch (Jarriault et al.1. and components of the transcriptional activation complex that includes the intracellular domain. Tax and Thomas. elegans has been important in identifying such components... particularly of the site 3 (transmembrane domain) protease complex. Genetic analysis in C.LIN-12/Notch signaling in C. 1998) demonstrated ligand-dependent cleavage and nuclear translocation correlated with signal transduction. Tamura et al. Tax and Thomas. Mechanism of LIN-12/Notch signal transduction... elegans and other systems. Another C. 1995. 1996).. Roehl et al.. 1995).

2004). elegans has been instrumental in identifying these components and in illuminating their roles. which binds to and stabilizes the Presenilin holoprotein... elegans presenilin. Rooke et al. 1999). 1998.. 2000). sel-12 encodes a Presenilin. elegans (Levitan et al. The C. Analysis of SEL-12 revealed what is now generally accepted as the topology of Presenilin: eight membrane-spanning segments with a large cytosolic loop between the sixth and seventh transmembrane domains (Li and Greenwald. 1997. were identified in a screen for mutations that result in synthetic phenotypes when combined with loss of sel-12 or aph-2 activity (Francis et al. elegans established that Presenilin activity is critical for LIN-12/Notch signaling (Li and Greenwald. These two transmembrane domains contain conserved aspartyl residues that appear to be the catalytic aspartates of the protease (Kopan and Goate. 1998.2. 2000). sup-17 and adm-4 are functionally redundant for at least a subset of LIN-12/Notch mediated decisions in C.. The ortholog of APH-2 is Nicastrin. 2005). 1997). but there may also be additional redundant proteases that can mediate the extracellular cleavage (Jarriault and Greenwald. at about the same time. elegans. sup-17 is a positive factor for lin-12/Notch activity and appears to function cell autonomously. aph-1 and aph-2 (Goutte et al. 2004).LIN-12/Notch signaling in C. SEL-12/Presenilin is believed to be the catalytic subunit of the γ-secretase protease complex (Kopan and Goate. 4. which was also identified as a genetic locus in familial early-onset Alzheimer's disease (Yu et al.. adm-4. hop-1. 2004b. Kuzbanian.. Its Drosophila homolog. and has been termed "γ-secretase" (Kopan and Goate. Site 3 (transmembrane) cleavage The protein complex that mediates the site 3 cleavage of LIN-12/Notch also mediates the transmembrane cleavage of the β-amyloid precursor protein (β-APP). Thinakaran et al. 2000.. 1996. Pen-2 then associates with this tripartite complex to confer γ-secretase activity (reviewed in Iwatsubo. 5 . was also implicated in Notch signaling (Pan and Rubin. Endoproteolysis in the cytosolic loop of SEL-12/Presenilin (Li and Greenwald.. DSL-1... Genetic analysis in C. 1997. and genetic analysis of these genes in C. Goutte et al. Site 2 (extracellular) cleavage sup-17 was identified as a suppressor of the 0 AC defect caused by lin-12(d) mutations (Tax et al. 1997). 4. 1997) and found to encode a metalloprotease of the ADAM family (Wen et al..3. appears to be functionally redundant with sel-12.. was shown to be a secreted protein that is functionally redundant with lag-2 and apx-1 in LIN-12-mediated vulval precursor cell fate specification (Chen and Greenwald. Mutations that confer the anterior pharynx (Aph) defect resulting from failure of glp-1 signaling at the 12 cell stage of embryogenesis yielded two genes. although deletion of this region does not appreciably abrogate Presenilin activity in C. 2002) Biochemical analysis. 2000). 2003). see also Vulval development). a different ADAM protein. The first evidence of a link between the LIN-12/Notch and β-APP transmembrane cleavage events came from the recovery of sel-12 as a suppressor of lin-12(d) (Levitan and Greenwald. 1996. 1996) is facilitated by Pen-2 and is believed to be essential for γ-secretase activity (reviewed in Iwatsubo. elegans the new predicted ligands. elegans yielded the other three components of γ-secretase. see Figure 3). also appears to be a positive factor for lin-12/Notch activity in some cell fate decisions. has been implicated in the site 2 cleavage (Brou et al. Li and Greenwald. Westlund et al. in mammals. However. principally in mammalian cell culture. Sotillos et al. 1995). 1996. but there has not been a direct demonstration of its involvement in the site 2 cleavage. 2000). has suggested that Nicastrin and Aph-1 form an initial complex. been identified as a major genetic locus in familial early-onset Alzheimer's disease (Sherrington et al. Four proteins are sufficient to reconstitute γ-secretase activity in yeast (Edbauer et al. 1995). TACE... A second C. 1996). elegans TACE ortholog. 2000). Other genetic screens in C. 2002). aph-1 as well as the fourth component of γ-secretase. which had. pen-2.

elegans LAG-2. APX-1. In Drosophila the genetic evidence suggests that Kuzbanian alone may mediate S2 cleavage (Rooke et al.. TACE has been demonstrated to cleave Notch in biochemical assays (Brou et al. We note that placement of SUP-17 at this step is consistent with available genetic information and with the Drosophila data.g. elegans Figure 3. elegans Presenilins (PS). There is evidence for functional redundancy of sup-17 and adm-4 (TACE) in C. Core components of the LIN-12/Notch pathway Role Ligand Receptor Site 2 cleavagea C. the seven-pass transmembrane protein APH-1. which are both essential for lin-12 and glp-1 activity (Lambie and Kimble. Delta-like. Serrate Notch Kuzbanian (TACE) Presenilin (Aph-1) Nicastrin (Pen-2) Su(H) Mastermind Mammals Jagged.. Core component complexes. although sup-17 appears to have a more significant role (Jarriault and Greenwald. Pan and Rubin. and the single-pass transmembrane protein APH-2/Nicastrin are described in the text. Kuzbanian and ADAM-10 appear to be orthologs of each other. GLP-1 SUP-17 ADM-4 SEL-12. Orthology is defined by BLAST searching and phylogenetic analysis (e. 2000. also known as LAG-3.. 2005). Petcherski and Kimble. The SEL-12/Presenilin (γ-secretase) complex.LIN-12/Notch signaling in C. 1991. and are paralogs of TACE. Transmembrane domains 6 and 7 contain catalytic aspartyl residues (represented by shading).. elegans. Doyle et al. 6 . 2000). B. adopt an eight transmembrane domain topology and are cleaved into N-terminal (PS NTF) and C-terminal (PS CTF) fragments. all are proteases of the ADAM family.. first published in Tax et al. 1996. SEL-12 and HOP-1. HOP-1 APH-1 APH-2 PEN-2 LAG-1 SEL-8b Drosophila Delta. The intracellular domain of LIN-12 or GLP-1 forms a ternary complex with LAG-1 and SEL-8. but genetic analysis is consistent with functionally redundant proteases and ADAM10 involvement. Tax et al. The LIN-12/Notch activation complex. DSL-1. 2 APH-1 Nicastrin PEN-2 CBF1/RBP-J Mastermind-like Site 3 cleavage Nuclear complex a SUP-17. 2005).1997. as in Jarriault and Greenwald. In mammals. The contributions of the two-pass transmembrane protein PEN-2. ADM-4 and TACE also appear to be orthologs. 1997. 2000). A. the C. (1997). Table 1. 1997). Sottilos et al. 4 others Notch 1–4 (ADAM-10) TACE Presenilin 1. b Official name.. 7 others LIN-12.

. submitted).. because their genetic behavior as a suppressor or enhancer depends on the nature of the lin-12 allele with which they are combined. elegans. 2001. 5.. with the insertion of an unusual beta-trefoil domain (Kovall and Hendrickson. LAG-1 appears to have the same binding specificity as its orthologs (Christensen et al. 1997. Suppressors of lin-12(d) In lin-12(d) mutants. and SEL-8/Mastermind--are believed to be the core of the transcriptional activation complex formed when LIN-12/Notch is activated (Figure 3. Morel and Schweisguth. Petcherski and Kimble (2000b) proposed that SEL-8 serves the same function as Drosophila and mammalian Mastermind. CSL proteins are DNA binding proteins that are part of the transcriptional activation complex that forms with the LIN-12/Notch intracellular domain (see also Figure 3)... For the purposes of this discussion. 2000). Based on fact that both SEL-8 and Mastermind have glutamine-rich stretches.. but not saturated. 1995). Association with the LIN-12/Notch intracellular domain is believed to lead to transcriptional activation in two steps: first by displacing corepressors.. leading to the acronym CSL for this family of DNA binding proteins (Christensen et al. Mastermind has been well-characterized as an integral part of the complex that binds DNA (Kitagawa et al. At this time. The nuclear complex As mentioned above. which is recruited by association with Mastermind.. which play more general roles in transcriptional activation. 2002). Strong hypomorphic and null alleles of lag-1 were recovered in a screen for mutations that cause a Lag phenotype. sel-8 encodes a novel.... glutamine rich. elegans 4. In some cases. 5. then by recruiting coactivators (Hsieh et al. 1996) Indeed. and the observation that both form ternary complexes with the intracellular domains of LIN-12/Notch and CSL proteins. 1996). The crystal structure of LAG-1 complexed with target DNA revealed that the amino and carboxy-terminal domains are strikingly similar to a region oftranscription factors of the NF-κB/Rel family. these three components--the intracellular domain of LIN-12/Notch.. Extensive. Identification of modulators of lin-12 and glp-1 activity Various genetic screens have identified many modulators of lin-12 and glp-1 activity. a CSL protein. In C. CSL proteins have transcriptional repressor activity. providing a structural basis for the switch between repressor and activator forms (Kovall and Hendrickson.LIN-12/Notch signaling in C. 2000). 2000a). leading to the absence of an AC. suggesting that lag-1 is a critical component of LIN-12/Notch signaling (Lambie and Kimble. weaker alleles of lag-1 have also been recovered in a screen for alleles that strongly increase the severity of a weak glp-1 loss-of-function phenotype in the germ line (Qiao et al. Prior to LIN-12/Notch activation. Mastermind may enhance phosphorylation and turnover of the Notch intracellular domain (Fryer et al. and the p300-associated protein PCAF (Fryer et al. 1996. The C. the CSL protein is called LAG-1. lag-1 was cloned and shown to be orthologous to Drosophila Su(H) and mammalian CBF1/RBP-J. 2002). are named "sel" (suppressor/enhancer of lin-12).g. Many of the sel genes also interact genetically with glp-1. Wu et al. 1991). Jarriault et al. and SKIP. Tax et al. it was referred to as LAG-3 in this study (Petcherski and Kimble. Fryer et al.. I consider a modulator to be any gene whose activity influences lin-12 and/or glp-1 activity. excess lin-12 activity alters a cell fate decision during gonadogenesis (see below). Among the proteins recruited are CBP/p300.. SEL-8 was also identified based on the formation of a ternary complex with LAG-1 and the intracellular domain of GLP-1 in yeast. 2000).1. In addition to contributing to transcriptional activation of target genes. Most genes recovered in these screens. submitted).. but whose gene product has not been established to be a core component. In addition.. and genetic analysis in Drosophila has established distinct roles for transcriptional repression by CSL proteins in development (e. and in the screen for suppressors of a lin-12 hypomorph (see below).. Katic et al. are recruited through interactions with this core complex. which physically associates with both CBF1 and the Notch intracellular domain (Zhou et al.4. 7 . screens for extragenic suppressors of this egg-laying defect have been performed (Greenwald et al. and consequently to an inability to lay eggs. nuclear protein (Doyle et al.. 2000). The beta-trefoil domain appears to have roles in both the recognition of target DNA and in mediating mutually-exclusive interactions with either corepressors or the intracellular domain of LIN-12/Notch. 1997). 2004). 1995) and in screens for suppression of the 0 AC defect caused by a lin-12(d) mutation (Katic et al. new information may at some future date lead to reclassification. 1983. Numerous other proteins. 2002). 2004). elegans transcription activation complex also is likely to contain SEL-8 (Figure 3). A single non-null allele of sel-8 was identified as a suppressor of the 0 AC defect caused by a lin-12(d) mutation (Tax et al.

Table 2. Modulators of lin-12 and glp-1 activity. a serine/threonine kinase (Fares and Greenwald.. but proteins divergent in sequence may perform equivalent functions. in preparation. 2000). Wu et al. Other suppressors of glp-1 sterility proved to be genes required for body morphology. which encodes a carbohydrate modifying enzyme that is homologous to Drosophila Brainiac (Griffitts et al. This strategy was used to screen for enhancers of the partial germline proliferation defect of a weak glp-1 loss-of-function mutation and yielded five ego genes. 2003). Enhancers of a glp-1 hypomorph Partial loss of glp-1 activity provides a sensitized background to search for genes that promote glp-1 activity. for enhancers of glp-1 (one). 1997). 2001.2. sel-9 encodes a p24 protein involved in quality control of membrane protein trafficking (Wen and Greenwald. and therefore may influence gene expression at the transcriptional level (E. and encodes an RNA-directed RNA polymerase (Smardon et al. Suppressors of a lin-12 hypomorph Reversion of the egg-laying defect caused by partial loss of lin-12 activity yielded five genes (Sundaram and Greenwald. for suppressor of glp-1. Oberg et al.LIN-12/Notch signaling in C. 1999).. ego-1 mutants are resistant to RNAi. as well as weak alleles of lag-1 (Qiao et al. a novel nuclear protein (Chen et al. 1996. sel-10 encodes an E3 ubiquitin ligase that forms a complex with the intracellular domain of LIN-12 (Hubbard et al. SEL-7 contains no recognizable amino acid sequence motifs and has only nematode orthologs. which may indicate that the extracellular matrix influences glp-1 activity in the germ line (Maine and Kimble. None of these have been molecularly characterized. Howell and J.. 2001). and SEL-6. personal communication) identified ten sog genes. as reducing the activity of such genes will cause a synthetic Glp sterile phenotype. 2004a).. 1997..M.3. sup-17 and lag-1. Maine and 8 . 2002). SPR-3 and SPR-4 contain zinc fingers (Lakowski et al. 1999)... ego-1 plays multiple roles in germline development. Priess.. elegans In addition to alleles of the core component genes lag-2. 1993). 1993). 5. Grant and Greenwald. Tables 2 and 3). Genes listed here have displayed a genetic interaction with both lin-12 and glp-1 in at least one cell fate decision. a AAA-ATPase (Katic and Greenwald... Urano et al.. Table 2). suggesting a link between germline development and cellular processes involved in post-transcriptional silencing (Smardon et al.. Role Inferred regulatory role + C. Three have been characterized in detail (Table 2). Suppressors of glp-1 hypomorph Screens for suppressors of the germline defect caused by loss of zygotic glp-1 activity (Maine and Kimble. Smardon et al. sel-8. 1995. and several additional. SEL-7. Studies of mammalian orthologs have demonstrated that SEL-10 promotes the ubiquitin-mediated turnover of the intracellular domain of LIN-12/Notch proteins via phosphorylation of the PEST domain (Gupta-Rossi et al. 5. This screen has also yielded a loss-of-function allele of bre-5. 2001. 2000). sel-1 encodes a protein that is involved in endoplasmic reticulum-associated protein degradation (Grant and Greenwald. 5. elegans SEL-7 SPR-1 SPR-2 SPR-3 SPR-4 SPR-5 SEL-1 SEL-9 SEL-10 Mammals ?a CoREST Set/Nap ? ? p110b Sel-1 p24 Sel-10/Fbw7 Nuclear/ target genes - ERAD/ quality control Stability a - ? = no apparent mammalian ortholog based on amino acid sequence identity. the screen for lin-12(d) suppressors has yielded mutations in genes for SEL-5. submitted).. ego-1 also promotes heterochromatin assembly. 2001).4. as yet uncloned genes (Katic et al. 1993) or of the embryonic lethality caused by loss of maternal glp-1 activity (A. 2000.

6. The archetypal example of lateral specification in C. atx-2 acts independently of GLP-1 signaling and in translational regulation in the germline (Ciosk et al. The teg genes are currently being analyzed in detail. via LAG-2 and LIN-12.. A screen for enhancers of a weak tumorous phenotype caused by mild glp-1 gain-of-function has identified tumorous enhancers of glp-1 (teg genes). Enhancers of glp-1 gain-of-function Strong activation of glp-1 in the germ line results in continued mitotic proliferation without meiosis. Schedl. elegans embryo. initially express both lin-12 and lag-2. but proteins divergent in sequence may perform equivalent functions. but a small initial difference in lin-12 activity is 9 . and cells further away selecting another. Maine et al. Recent analysis of ego-5 suggests that regulation of DNA replication proteins may be part of the switch from mitotic to meiotic development (E. Induction occurs when equivalent cells choose alternative fates in response to an external source of ligand.. Suppressors of the egg-laying defective phenotype of sel-12 mutants identified spr genes (suppressors of presenilin. so that only one becomes the AC. The CoREST complex may be involved in the balance of repression and activation of lin-12 target genes or in regulating expression of a limiting component required for lin-12 activity.. called the "tumorous" phenotype. 2004. During the "AC/VU decision". 1997). LIN-12/Notch proteins appear to be unique mediators of lateral specification during animal development. SPR-4 and SPR-5.LIN-12/Notch signaling in C. Hansen and T. A key concept of general significance that emerged from studies of this decision is the importance of a feedback mechanism that drives the cells to adopt different fates: both Z1.. with cells close to the source selecting one fate. elegans EGO-1 SEL-2 SEL-5 BRE-5 Mammals ?a Neurobeachin AAK1 Brainiac glycosyltransferase ? = no apparent ortholog based on amino acid sequence identity. sel-10 also suppresses the egg-laying defect of sel-12 mutants.. The gene atx-2 was also identified by RNAi as an ego gene and found to be required for germline proliferation (Ciosk et al. All possible interactions have not necessarily been tested. personal communication). Maine et al. 2004). Some of these interactions are considered elsewhere in WormBook (see Notch signaling in the C. and Germline proliferation and its control) and so have not been catalogued here. 1998). Lakowski et al. elegans development. elegans W. suggesting that sel-10 may regulate lin-12 activity through regulating SEL-12 as well LIN-12 levels (Wu et al. 2001). Lateral specification and induction mediated by LIN-12 and GLP-1 LIN-12 and GLP-1 mediate many different cell-cell interactions during C. Lateral specification (lateral inhibition) occurs when a group of equivalent cells interact among themselves to specify alternative cell fates. Maine. Kelly. 2004. 2002. Modulator of: glp-1 lin-12 lin-12 lin-12 a Inferred regulatory role + + + C. 2003). Genes listed here have displayed a genetic interaction with either lin-12 or glp-1. 2002. The two general categories of cell-cell interactions are lateral specification and induction. personal communication). four of which (SPR-1. elegans involves a cell fate decision between the anchor cell (AC) and ventral uterine precursor cell (VU) fates in early gonadogenesis in hermaphrodites. potential negative regulators of glp-1 activity in the germ line (D.. Hermaphrodite cell-fate specification. 5. hop-1 (Li and Greenwald.. The two cells interact with each other.6.. Male development. 2004).ppp and Z4. 2000).. Jarriault and Greenwald. two equivalent cells each have the potential to become an AC or a VU. Suppressors of Presenilin sel-12 null alleles are unable to lay eggs because of a defect in lin-12-mediated π cell specification (Cinar et al.5. personal communication). Wen et al. Table 2) appear to be members of a CoREST-containing corepressor complex (Eimer et al. and SEL-10 forms a complex with SEL-12. 5. Table 3. Modulators of lin-12 or glp-1 activity. sel-12 null mutants are viable because they retain activity of a second presenilin gene. Vulval development.

Iskra Katic. J. L.. in C. and Kimble. Lisa Girard. in the presumptive 1° VPC.. 1996).... For example. Bob Johnston. One approach to answering this question is the identification and characterization of target genes--and one fruitful approach to identifying target genes is computational analysis to identify genes that contain potential LAG-1 binding sites in regulatory regions (Yoo et al. In the presumptive 1° VPC. The roles of glp-1 in germline development (see Specification of the germ line) and pharyngeal induction are canonical inductive interactions: ligands produced in the distal tip cell of the somatic gonad activate GLP-1 in the germ line (Henderson et al. 2004b). LIN-12 activation by LAG-2 positively autoregulates lin-12 transcription and downregulates lag-2 transcription (Wilkinson et al. Tim Schedl. activation of LET-23 leads to transcription of DSL ligand genes (Chen and Greenwald. and Gary Struhl for helpful comments on the manuscript. and ligands produced in one embryonic founder cell activate GLP-1 in descendants of another (Mickey et al. the emphasis has been shifting to understanding how signaling is modulated. There are likely to be many ways in which feedback modulation is achieved. 1994). In the presumptive 2° VPCs. receptor activity is essentially regulated by where the ligand is expressed or activated. Yoo et al. During germline development. I am an Investigator of the Howard Hughes Medical Institute. cross-regulatory interactions between the LET-23/EGF receptor-Ras-MAP kinase pathway and LIN-12 ensure that the central three vulval precursor cells (VPCs) adopt the correct pattern of fates. must occur for the DSL ligands to be active (Shaye and Greenwald. 2003).. In these cases. ligand expression per se is not sufficient to activate LIN-12 in the flanking VPCs. 2001. 1994). However. Cell 51. 925–936. Eleanor Maine. like many other receptor systems. The latter step appears to involve post-transcriptional downregulation of HLH-2. 1996. Another important question for the future is how activation of LIN-12/Notch specifies different cell fate choices. glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. Shelton and Bowerman. there appears to be post-transcriptional up-regulation of GLP-1 accumulation (Berry et al. 2004)..W. 589–599. (1997). also in response to LET-23 activation. Westlund. In the presumptive VU. feedback mechanisms.. elegans. elegans. in response to LIN-12 activation (Karp and Greenwald. effectively squelching input from the inductive signaling pathway (Berset et al. Germ-line tumor formation caused by activation of glp-1. there appear to be feedback mechanisms that affect receptor expression or activity. endocytosis-mediated downregulation of LIN-12. One aspect is understanding how signaling is modulated in response to LIN-12/Notch activation itself. Future prospects With the core signal transduction mechanism largely elucidated. Acknowledgements Thanks to Marty Chalfie. References Austin. is likely to involve modulation of signaling by transcriptional and post-transcriptional mechanisms. LIN-12/Notch proteins. 9. other signaling inputs. Modulation is likely to involve different mechanisms for post-transcriptional regulation as well. Abstract 10 . However. 2000). a Caenorhabditis elegans member of the Notch family of receptors. and integrated with.. elegans amplified by reciprocal feedback loops in the presumptive AC and presumptive VU (Seydoux and Greenwald. Development 124. and Schedl. J. Jim Priess. Regulatory mechanisms integrate LIN-12/Notch signaling with other signaling events during animal development. T. Sophie Jarriault. also mediate inductive interactions during development. represented as 2°-1°-2° (see Vulval development). i. Work on the identification of genes that influence lin-12/Notch activity in my lab is supported by NIH CA095389. a transcription factor required for lag-2 transcription.. in addition. too. (1987). 8. activation of LIN-12 leads to transcription of target genes that encode negative regulators of the EGF receptor-Ras-MAP kinase pathway. This aspect.. B.. 1997). and activation of LIN-12 by LAG-2 leads to downregulation of lin-12 transcription (Hermann etal. Wilkinson et al. 2004). Abstract Article Berry. 1989. even when ligand originates externally. 2002). Another aspect is understanding how LIN-12/Notch signaling is influenced by. 1994). elegans embryo). 7. LAG-2-expressing cells.e. Another intriguing example is afforded by the lin-12-mediated generation of morphological twist of the intestinal tube: twist is initiated when the cells in the left half of the intestinal primordium contact external. Transcriptional regulation may involve different transcriptional regulatory circuits (see Notch signaling in the C.LIN-12/Notch signaling in C.

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