NORMAL GENOMIC

• Dodd RB, Drickamer K
• Lectin-like proteins in model organisms: implications for evolution of carbohydrate-binding activity.
• Glycobiology. 2001; 11: 719-719
• Display abstract

• Classes of intracellular lectins that recognize core-type structures and mediate intracellular glycoprotein trafficking are present in vertebrates, model invertebrates such as Caenorhabditis elegans and Drosophila melanogaster, plants, and yeasts. Lectins that recognize more complex structures at the cell surface, such as C-type lectins and galectins, are also found in invertebrate organisms as well as vertebrates, but the functions of these proteins have evolved differently in different animal lineages.

• Goutte C, Hepler W, Mickey KM, Priess JR
• aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling.
• Development. 2000; 127: 2481-92
• Display abstract

• In animal development, numerous cell-cell interactions are mediated by the GLP-1/LIN-12/NOTCH family of transmembrane receptors. These proteins function in a signaling pathway that appears to be conserved from nematodes to humans. We show here that the aph-2 gene is a new component of the GLP-1 signaling pathway in the early Caenorhabditis elegans embryo, and that proteins with sequence similarity to the APH-2 protein are found in Drosophila and vertebrates. During the GLP-1-mediated cell interactions in the C. elegans embryo, APH-2 is associated with the cell surfaces of both the signaling, and the responding, blastomeres. Analysis of chimeric embryos that are composed of aph-2(+) and aph-2(-) blastomeres suggests that aph-2(+) function may be provided by either the signaling or responding blastomere.

• Doyle TG, Wen C, Greenwald I
• SEL-8, a nuclear protein required for LIN-12 and GLP-1 signaling in Caenorhabditis elegans.
• Proc Natl Acad Sci U S A. 2000; 97: 7877-81
• Display abstract

• LIN-12 and GLP-1 are members of the LIN-12/Notch family of receptors that mediate cell-cell interactions during development. The sel-8 gene had been identified previously in a screen for suppressors of a mutation that constitutively activates LIN-12. Here, we report that sel-8 is essential for lin-12- and glp-1-mediated signaling, and that SEL-8 is a glutamine-rich nuclear protein. We postulate that SEL-8 serves as a transcriptional coactivator or as an assembly factor for transcription complexes that contain the LIN-12 or GLP-1 intracellular domains.

• Bejsovec A
• Wnt signalling shows its versatility.
• Curr Biol. 1999; 9: 6847-6847
• Display abstract

• Wnt signalling controls many different cell fate choices in a wide variety of animal species. Recent studies have revealed that regulatory interactions at several steps in the pathway can modify its outcome, helping to explain how the same pathway can, in different contexts, have very different characteristics and consequences.

• Matsuno K
• [Molecular mechanisms and developmental functions of notch signaling]
• Tanpakushitsu Kakusan Koso. 1999; 44: 19-31

• Egan SE, St-Pierre B, Leow CC
• Notch receptors, partners and regulators: from conserved domains to powerful functions.
• Curr Top Microbiol Immunol. 1998; 228: 273-324

• Zeng C, Younger-Shepherd S, Jan LY, Jan YN
• Delta and Serrate are redundant Notch ligands required for asymmetric cell divisions within the Drosophila sensory organ lineage.
• Genes Dev. 1998; 12: 1086-91
• Display abstract

• Asymmetric divisions allow a precursor to produce four distinct cells of a Drosophila sensory organ lineage (SOL). Whereas this process requires cell-cell communication via Notch (N) receptor, mitotic recombination that removes the N ligand Delta (Dl) or Serrate (Ser) in the SOL had mild or no effect. Removal of both Dl and Ser, however, led to cell fate transformations similar to the N phenotype. Cell fate transformation occurred even when a single SOL cell lost both Dl and Ser. Thus, Dl and Ser are redundant in mediating signaling between daughter cells to specify their distinct cell fates.

• Greenwald I
• LIN-12/Notch signaling: lessons from worms and flies.
• Genes Dev. 1998; 12: 1751-62

• Henderson ST, Gao D, Christensen S, Kimble J
• Functional domains of LAG-2, a putative signaling ligand for LIN-12 and GLP-1 receptors in Caenorhabditis elegans.
• Mol Biol Cell. 1997; 8: 1751-62
• Display abstract

• The LAG-2 membrane protein is a putative signaling ligand for the LIN-12 and GLP-1 receptors of Caenorhabditis elegans. LAG-2, like its Drosophila homologues Delta and Serrate, acts in a conserved signal transduction pathway to regulate cell fates during development. In this article, we investigate the functional domains of LAG-2. For the most part, mutants were constructed in vitro and assayed for activity in transgenic animals. We find a functional role for all major regions except one. Within the extracellular domain, the N-terminal region, which bears no known motif, and the DSL domain are both required. By contrast, the region bearing epidermal growth factor-like repeats can be deleted with no apparent reduction in rescuing activity. The intracellular region is not required for activity but instead plays a role in down-regulating LAG-2 function. Finally, membrane association is critical for mutant rescue.

• Blaumueller CM, Artavanis-Tsakonas S
• Comparative aspects of Notch signaling in lower and higher eukaryotes.
• Perspect Dev Neurobiol. 1997; 4: 325-43
• Display abstract

• The Drosophila melanogaster Notch gene encodes a receptor that is part of a cell-cell signaling mechanism that is used throughout the development of the fly to regulate a wide variety of cell fate decisions, including some neuronal decisions. The Caenorhabditis elegans Notch-like genes lin-12 and glp-1 play roles that are similar to that of Notch, and studies of this signaling pathway in both organisms have led to models of how the pathway might function. Recent developments in the study of Notch signaling include the isolation of Notch homologs from a variety of vertebrate species. Here we compare what has been learned from studies of Notch-related genes in vertebrates to what is known about Notch signaling in invertebrates, and we discuss the implications of these data for existing models of Notch pathway signaling.

• Wen C, Metzstein MM, Greenwald I
• SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling.
• Development. 1997; 124: 4759-67
• Display abstract

• LIN-12/NOTCH proteins mediate cell-cell interactions that specify cell fates. Previous work suggested that sup-17 facilitates lin-12 signalling in Caenorhabditis elegans. Here, we show that sup-17 encodes a member of the ADAM family of metalloproteases. SUP-17 is highly similar to Drosophila KUZBANIAN, which functions in Drosophila neurogenesis, and the vertebrate ADAM10 protein. Furthermore, we show by genetic analysis that the extracellular domain of LIN-12 appears to be necessary for sup-17 to facilitate lin-12 signalling and that sup-17 does not act downstream of lin-12. Finally, we show by cell ablation experiments that sup-17 can act cell autonomously to facilitate lin-12 activity. We discuss the implications of our observations for LIN-12/NOTCH signalling and how our results complement and extend results obtained from genetic analysis of kuz in Drosophila.

• Lambie EJ
• Nematode development: evolutionary detours of a pivotal cell.
• Curr Biol. 1997; 7: 1603-1603
• Display abstract

• The anchor cell plays a central role in organizing the reproductive structures of the nematode Caenorhabditis elegans. Recent studies show that significant alterations in the origin, function and fate of this key regulatory cell have occurred during the course of nematode evolution.

• Hubbard EJ, Wu G, Kitajewski J, Greenwald I
• sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins.
• Genes Dev. 1997; 11: 3182-93
• Display abstract

• Mutations that influence lin-12 activity in Caenorhabditis elegans may identify conserved factors that regulate the activity of lin-12/Notch proteins. We describe genetic evidence indicating that sel-10 is a negative regulator of lin-12/Notch-mediated signaling in C. elegans. Sequence analysis shows that SEL-10 is a member of the CDC4 family of proteins and has a potential human ortholog. Coimmunoprecipitation data indicate that C. elegans SEL-10 complexes with LIN-12 and with murine Notch4. We propose that SEL-10 promotes the ubiquitin-mediated turnover of LIN-12/Notch proteins, and discuss potential roles for the regulation of lin-12/Notch activity by sel-10 in cell fate decisions and tumorigenesis.

• Berry LW, Westlund B, Schedl T
• Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors.
• Development. 1997; 124: 925-36
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• Caenorhabditis elegans germ-line proliferation is controlled by an inductive interaction between the somatic distal tip cell and the germ line. GLP-1, a member of the Notch family of transmembrane receptors, is required continuously in the germ line to transduce the proliferative signal. In the absence of GLP-1, all proliferative germ cells exit the mitotic cell cycle and enter meiotic prophase. We have characterized an activating mutation in glp-1, oz112gf, that has the opposite phenotype. Homozygous glp-1(oz112gf) hermaphrodites and males have a completely tumorous germ line in which germ cells never leave the mitotic cycle. In glp-1(oz112gf) heterozygotes, germ-line polarity is established correctly, but as adults age, the distal proliferative population expands leading to a late-onset tumorous phenotype. The mutant receptor is constitutively active, promoting proliferation in the absence of ligand. The normal distal-proximal spatial restriction of GLP-1 expression is lost in tumorous and late-onset tumorous animals; ectopically proliferating germ cells contain membrane-associated GLP-1. The correlation between proliferation and expression, both in wild-type where glp-1 signalling is limited by localized ligand and in glp-1(oz112gf) where signalling is ligand-independent, suggests that glp-1 signalling positively regulates GLP-1 expression. In addition to germ-line defects, glp-1(oz112gf) causes inappropriate vulval cell fate specification. A missense mutation in a conserved extracellular residue, Ser642, adjacent to the transmembrane domain, is sufficient to confer the glp-1(oz112gf) mutant phenotypes. Two mammalian Notch family members, TAN-1 and int-3, are proto-oncogenes. Thus, activating mutations in both invertebrate and vertebrate Notch family members can lead to tumor formation.

• Young MW, Wesley CS
• Diverse roles for the Notch receptor in the development of D. melanogaster.
• Perspect Dev Neurobiol. 1997; 4: 345-55
• Display abstract

• Notch proteins appear to be involved in cell fate commitments with deep evolutionary roots. Homologues have been shown to play key roles in the development of nematodes, insects, amphibia, and mammals. Activity of the Notch receptor has been observed in the patterning of ectoderm, mesoderm, and endoderm, indicating an origin prior to the functional differentiation of these germ layers. To understand how a single receptor can participate so widely in development, we have been examining the role of specific extracellular segments of Notch. Early studies of mutations affecting widely separated EGF-like elements of Notch first raised the possibility for interaction with multiple ligands. Biochemical approaches, and exhaustive structure function studies in transgenic Drosophila are beginning to reveal how this receptor is activated, and point to a range of physical interactions with other proteins.

• Perrimon N
• Serpentine proteins slither into the wingless and hedgehog fields.
• Cell. 1996; 86: 513-6

• Christensen S, Kodoyianni V, Bosenberg M, Friedman L, Kimble J
• lag-1, a gene required for lin-12 and glp-1 signaling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H).
• Development. 1996; 122: 1373-83
• Display abstract

• The homologous receptors LIN-12 and GLP-1 mediate diverse cell-signaling events during development of the nematode Caenorhabditis elegans. These two receptors appear to be functionally interchangeable and have sequence similarity to Drosophila Notch. Here we focus on a molecular analysis of the lag-1 gene (lin-12 -and glp-1), which plays a central role in LIN-12 and GLP-1-mediated signal transduction. We find that the predicted LAG-1 protein is homologous to two DNA-binding proteins: human C Promoter Binding Factor (CBF1) and Drosophila Suppressor of Hairless (Su(H)). Furthermore, we show that LAG-1 binds specifically to the DNA sequence RTGGGAA, previously identified as a CBF-1/Su(H)-binding site. Finally, we report that the 5' flanking regions and first introns of the lin-12, glp-1 and lag-1 genes are enriched for potential LAG-1-binding sites. We propose that LAG-1 is a transcriptional regulator that serves as a primary link between the LIN-12 and GLP-1 receptors and downstream target genes in C. elegans. In addition, we propose that LAG-1 may be a key component of a positive feedback loop that amplifies activity of the LIN-12/GLP-1 pathway.

• Seugnet L, Simpson P
• [Role of the Notch receptors in intercellular communication]
• Pathol Biol (Paris). 1996; 44: 282-6
• Display abstract

• The Notch gene was discovered in Drosophila at the beginning of the century and is currently the subject of intensive investigation, not only in invertebrates but also in vertebrates where remarkably well conserved homologues have been recently found. Notch encodes a new kind of cellular receptor whose functioning is still unclear and plays a role in a large number of cell interactions throughout development and in tissue renewal in the adult. Detailed study in invertebrates of some of these interactions has led to the identification of other genes required for transduction of the signal initiated by the receptor. Notch is always involved in processes where cells have the potential to choose between several different programmes of differentiation. Cells adopt a specific developmental pathway as a result of the inhibition of some programmes through Notch signalling. In this review we discuss the contribution of different experimental models to an understanding of the role of Notch in intercellular signalling.

• Moskowitz IP, Rothman JH
• lin-12 and glp-1 are required zygotically for early embryonic cellular interactions and are regulated by maternal GLP-1 signaling in Caenorhabditis elegans.
• Development. 1996; 122: 4105-17
• Display abstract

• Cell-cell interactions mediated by LIN-12 and GLP-1, members of the LNG (LIN-12, Notch, GLP-1) family of receptors, are required to specify numerous cell fates during development of the nematode Caenorhabditis elegans. Maternally expressed GLP-1 participates in two of at least four sequential inductive interactions that specify the fates of early embryonic descendants of the AB founder cell. We report that GLP-1 and LIN-12, and apparently their ligand, LAG-2, as well as a downstream component, LAG-1, are required in the latter two inductions. We find that LAG-2 is expressed in the signaling cells and LIN-12 is expressed in cells receiving the inductions, consistent with their proposed roles as ligand and receptor, respectively. Furthermore, we report that maternal GLP-1 activity is required (1) to repress early zygotic lag-2 expression and (2) to activate zygotic lin-12 expression in the early embryo. The patterning of both receptor and ligand expression by maternal GLP-1 signaling establishes competence for the zygotic LNG-mediated cellular interactions and localizes these interactions to the appropriate cells. We propose that activation of maternal GLP-1 regulates zygotic lin-12 and lag-2 expression by a regulatory mechanism analogous to that described for the post-embryonic gonad.

• Shelton CA, Bowerman B
• Time-dependent responses to glp-1-mediated inductions in early C. elegans embryos.
• Development. 1996; 122: 2043-50
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• In an embryo of the nematode Caenorhabditis elegans, two blastomeres at the 4-cell stage, ABa and ABp, are born with equivalent developmental potential. Subsequently, interactions with the P2 blastomere at the 4-cell stage and the MS blastomere at the 12-cell stage generate differences in developmental fate among descendants of ABa and ABp. We have reproduced these inductions in vitro using embryonic blastomeres isolated in cell-culture medium. We show that during these inductions only the responding AB descendants require the activity of the glp-1 gene, which is similar in sequence to Drosophila Notch, supporting models in which GLP-1 protein acts as a receptor for both the P2 and MS signals. We also show that P2 signaling requires the activity of the apx-1 gene, similar in sequence to Drosophila Delta, and that MS signaling requires the putative transcription factor SKN-1. We present evidence that the primary factor determining the different responses to these two signals is the age of the AB descendants, not the identity of the signaling cell or ligand. Therefore, we suggest that time-dependent changes in factors within AB descendants are responsible for their different responses to inductive signals that use a common receptor.

• Roush W
• Divide and confer: how worm embryo cells specialize.
• Science. 1996; 272: 1871-1871

• Hubbard EJ, Dong Q, Greenwald I
• Evidence for physical and functional association between EMB-5 and LIN-12 in Caenorhabditis elegans.
• Science. 1996; 273: 112-5
• Display abstract

• The Caenorhabditis elegans LIN-12 and GLP-1 proteins are members of the LIN-12/Notch family of receptors for intercellular signals that specify cell fate. Evidence presented here suggests that the intracellular domains of LIN-12 and GLP-1 interact with the C. elegans EMB-5 protein and that the emb-5 gene functions in the same pathway as the lin-12 and glp-1 genes. EMB-5 is similar in sequence to a yeast protein that controls chromatin structure. Hence, a direct consequence of LIN-12 or GLP-1 activation may be an alteration of chromatin structure that produces changes in transcriptional activity.

• Gao D, Kimble J
• APX-1 can substitute for its homolog LAG-2 to direct cell interactions throughout Caenorhabditis elegans development.
• Proc Natl Acad Sci U S A. 1995; 92: 9839-42
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• The homologous LAG-2 and APX-1 membrane proteins are putative signaling ligands in the GLP-1/LIN-12 signal-transduction pathway in Caenorhabditis elegans. Normally, LAG-2 and APX-1 mediate distinct cell interactions. Here, we demonstrate that APX-1, which normally interacts with GLP-1 in the early embryo, can substitute for LAG-2 throughout development. When expressed under control of the lag-2 promoter, an apx-1 cDNA can completely rescue a lag-2 null mutant. To substitute for LAG-2, APX-1 must be able to interact with both GLP-1 and LIN-12 receptors and to mediate a variety of cell interactions during development. Therefore, APX-1 and LAG-2 are essentially equivalent in their ability to influence receptor activity. On the basis of this result, we suggest that the existence of multiple-signaling ligands in the LIN-12/GLP-1 signal transduction pathway does not reflect the evolution of functionally distinct proteins but rather the imposition of distinct controls of gene expression upon functionally similar proteins. Finally, we propose that the specification of distinct cell fates by the LIN-12/GLP-1 signal-transduction pathway relies on activities functioning downstream of the ligand and receptor, rather than on specific ligand-receptor interactions.

• Lardelli M, Williams R, Lendahl U
• Notch-related genes in animal development.
• Int J Dev Biol. 1995; 39: 769-80
• Display abstract

• The Drosophila melanogaster gene Notch is central to many cell differentiation events during development. It encodes a large transmembrane signal receptor protein that acts in a poorly understood mechanism of communication affecting the choice of alternative differentiation fates by cells in close proximity. Genes with homology to Notch have been isolated from the nematode Caenorhabditis elegans and a number laboratories, including our own, have isolated multiple vertebrate Notch homologs. In this article we briefly outline the current state of research on Notch and our contribution to it. First, we examine the structure of Notch-related proteins. We then examine the requirements for Notch activity in the development of different organisms and how genetic and transgenic studies are helping us to understand the mechanism(s) by which these proteins function. We present models for the action of Notch receptors during signal transduction and for the interaction of multiple vertebrate Notch receptors. Finally, we discuss current ideas about the role played by Notch in differentiation and cell-cell communication.

• Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, Artavanis-Tsakonas S
• Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats.
• Development. 1995; 121: 2633-44
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• We present a molecular and genetic analysis which elucidates the role of deltex in the Notch signaling pathway. Using the yeast 'interaction trap' assay, we define the protein regions responsible for heterotypic interactions between Deltex and the intracellular domain of Notch as well as uncover homotypic interaction among Deltex molecules. The function of the Deltex-Notch interaction domains is examined by in vivo expression studies. Taken together, data from overexpression of Deltex fragments and from studies of physical interactions between Deltex and Notch, suggest that Deltex positively regulates the Notch pathway through interactions with the Notch ankyrin repeats. Experiments involving cell cultures indicate that the Deltex-Notch interaction prevents the cytoplasmic retention of the Suppressor of Hairless protein, which otherwise is sequestered in the cytoplasm via association with the Notch ankyrin repeats and translocates to the nucleus when Notch binds to its ligand Delta. On the basis of these findings, we propose a model wherein Deltex regulates Notch activity by antagonizing the interaction between Notch and Suppressor of Hairless.

• Winans KA, Hashimoto C
• Ventralization of the Drosophila embryo by deletion of extracellular leucine-rich repeats in the Toll protein.
• Mol Biol Cell. 1995; 6: 587-96
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• Dorsoventral polarity of the Drosophila embryo is established by a signal transduction pathway in which the maternal transmembrane protein Toll appears to function as the receptor for a ventrally localized extracellular ligand. Certain dominant Toll alleles encode proteins that behave as partially ligand-independent receptors, causing embryos containing these proteins to become ventralized. In extracts of embryos derived from mothers carrying these dominant alleles, we detected a polypeptide of approximately 35 kDa in addition to full-length Toll polypeptides with antibodies to Toll. Our biochemical analyses suggest that the smaller polypeptide is a truncated form of Toll lacking extracellular domain sequences. To assay the biological activity of such a shortened form of Toll, we synthesized RNA encoding a mutant polypeptide lacking the leucine-rich repeats that comprise most of Toll's extracellular domain and injected this RNA into embryos. The truncated Toll protein elicited the most ventral cell fate independently of the wild-type Toll protein and its ligand. These results support the view that Toll is a receptor whose extracellular domain regulates the intrinsic signaling activity of its cytoplasmic domain.

• Greenwald I
• Structure/function studies of lin-12/Notch proteins.
• Curr Opin Genet Dev. 1994; 4: 556-62
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• The lin-12/Notch proteins appear to act as transmembrane receptors for intercellular signals that specify cell fates during animal development. Recent structure/function studies have shown that the lin-12/Notch intracellular domain alone has the intrinsic signal-transducing activity of the intact protein, and that the role of the extracellular domain is to regulate this intrinsic activity. These studies have also suggested that the different lin-12/Notch proteins in a given organism are interchangeable biochemically and have addressed the role of lin-12/Notch genes in development.

• Henderson ST, Gao D, Lambie EJ, Kimble J
• lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans.
• Development. 1994; 120: 2913-24
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• The C. elegans lag-2 gene is required for several cell-cell interactions that rely on the receptors GLP-1 and LIN-12. In this paper, we report that lag-2 encodes a putative membrane protein with sequence similarity to Drosophila Delta, a proposed ligand for the Notch receptor. Furthermore, we show that the lag-2 promoter drives expression of a reporter protein in the signaling distal tip cell (DTC) of the DTC/germline interaction. By in situ hybridization, we have found that endogenous lag-2 mRNA is present in the DTC but not the germ line. One fusion protein, called LAG-2::beta-gal(intra), rescues a lag-2 null mutant and can be detected in both DTC and germ line. Taking these results together, we propose that lag-2 may encode a signaling ligand for GLP-1/LIN-12 and that the entire LAG-2 protein may be taken up into the receiving cell during induction by GLP-1 and lateral signaling by LIN-12.

• Wilkinson HA, Fitzgerald K, Greenwald I
• Reciprocal changes in expression of the receptor lin-12 and its ligand lag-2 prior to commitment in a C. elegans cell fate decision.
• Cell. 1994; 79: 1187-98
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• During development of the C. elegans hermaphrodite gonad, two cells interact with each other, so that one chooses to become the anchor cell (AC) and the other becomes a ventral uterine precursor cell (VU). This interaction is mediated by the receptor LIN-12 and its apparent ligand LAG-2. We show that initially lin-12 and lag-2 are expressed in both cells, but prior to commitment, the expression patterns change in a reciprocal manner, so that lin-12 expression becomes restricted to the presumptive VU and lag-2 expression becomes restricted to the presumptive AC. In addition, lin-12 activity promotes expression of lin-12 and represses expression of lag-2. Furthermore, we show that positive autoregulation of lin-12 transcription in the presumptive VU is mediated by a cis-acting 5' regulatory sequence and is necessary to specify the VU fate. Our results suggest that transcriptional control is a component of the feedback mechanism involved in specifying the AC and VU fates.

• Fortini ME, Artavanis-Tsakonas S
• The suppressor of hairless protein participates in notch receptor signaling.
• Cell. 1994; 79: 273-82
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• In a genetic screen for mutations that attenuate Notch signaling in the developing Drosophila eye, we isolated rare, gain-of-function alleles of Suppressor of Hairless (Su(H)), the fly homolog of the mammalian C promoter-binding factor 1 (CBF1) gene. Su(H) exhibits numerous allele-specific genetic interactions with Notch as well as with Delta, deltex, and mastermind. In cultured Drosophila cells, the Su(H) protein is sequestered in the cytoplasm when coexpressed with Notch protein and is translocated to the nucleus when Notch binds to its ligand Delta. Cytoplasmic retention of Su(H) requires the intracellular cdc10/ankyrin repeats of Notch, which associate with Su(H) protein in the yeast interaction trap assay. These results indicate that Notch activity may regulate nuclear events by controlling the activity of a DNA-binding protein.

• Struhl G, Fitzgerald K, Greenwald I
• Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo.
• Cell. 1993; 74: 331-45
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• The lin-12 gene of C. elegans and the Notch gene of D. melanogaster encode structurally related transmembrane proteins that mediate intercellular signaling. We show that truncated forms of these proteins consisting of only the intracellular domains cause cell fate transformations associated with constitutive activity in their respective organisms. This activity does not depend on endogenous gene function. Our results indicate that the intracellular domains of Lin-12 and Notch have intrinsic activity and that the principal role of the extracellular domains in the intact proteins is to regulate this activity. Our results also suggest that equivalent truncated forms of lin-12/Notch family members in vertebrates, including known oncogenes, are similarly active.

• Kimble J, Crittenden S, Lambie E, Kodoyianni V, Mango S, Troemel E
• Regulation of induction by GLP1, and localized cell surface receptor in Caenorhabditis elegans.
• Cold Spring Harb Symp Quant Biol. 1992; 57: 401-7

• Artavanis-Tsakonas S, Simpson P
• Choosing a cell fate: a view from the Notch locus.
• Trends Genet. 1991; 7: 403-8
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• During the development of Drosophila melanogaster, individual cells must make choices between a restricted set of possible fates in order to give rise to spatial patterns composed of different types of differentiated cells. The Notch locus appears to play a central and general role in the regulative events that control the local architecture of the final cellular pattern in several tissues, among them being the central and peripheral nervous systems.

• Mullins MC, Rubin GM
• Isolation of temperature-sensitive mutations of the tyrosine kinase receptor sevenless (sev) in Drosophila and their use in determining its time of action.
• Proc Natl Acad Sci U S A. 1991; 88: 9387-91
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• Loss-of-function mutations in the sevenless (sev) gene in Drosophila result in the failure to differentiate a specific photoreceptor cell type--namely, the R7 cell. The sev gene encodes a cell-surface receptor tyrosine kinase that functions in the presumptive R7 cell to transduce developmental cues from its neighbors, instructing it to differentiate along the R7 cell pathway. We have isolated temperature-sensitive alleles of sev and used them to show that Sev activity is required for several hours during the development of each R7 cell to specify R7 cell differentiation. Our data also suggest that the presumptive R7 cell remains for approximately 5 hr in an undetermined state in the absence of the Sev-mediated signal before committing to an alternative fate. We have determined the molecular lesions in four of the temperature-sensitive alleles. One of these mutations disrupts the Gly-Xaa-Gly-Xaa-Xaa-Gly consensus in the ATP-binding site of the kinase domain.

• Gay NJ, Keith FJ
• Drosophila Toll and IL-1 receptor.
• Nature. 1991; 351: 355-6