Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila

THE lin-12 and glp-1 genes of Caenorhabditis elegans encode members of the Notch family of transmembrane proteins1,2. Genetic studies indicate that the lin-12 and glp-1 proteins act as receptors in specific developmental cell interactions3–6 and that their functions are partially redundant7, lin-12 glp-1 double mutants display certain embryonic defects not found in either single mutant7,8. The phenotype of this double mutant is called Lag, and recessive mutations in either of the genes lag-1 or lag-2 can also result in the Lag phenotype7, indicating that these two genes may participate in the same cell interactions that require lin-12 or glp-1. We report here that lag-2 encodes a predicted transmembrane protein of 402 amino acids. The predicted extracellular region of lag-2 is similar to amino-terminal regions of Delta and Serrate, two Drosophila proteins that are thought to function as ligands for Notch9–14. The region of similarity includes sequences related to epidermal growth factor (EGF) repeats. We have isolated lag-2(sa37), a dominant allele that shows specific genetic interactions with lin-12. The sa37 mutation causes a Gly->Asp change in a conserved residue of an EGF motif. Because of its overall structure, its sequence similarity to Delta and Serrate, and its genetic interactions, we suggest that lag-2 encodes an intercellular signal for the lin-12 and glp-1 receptors.

[1]  H. Gainer,et al.  Proteolysis in neuropeptide processing and other neural functions. , 1984, Annual review of neuroscience.

[2]  J. Kimble,et al.  Transcript analysis of glp-1 and lin-12, homologous genes required for cell interactions during development of C. elegans , 1989, Cell.

[3]  P. Simpson,et al.  Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions. , 1993, Development.

[4]  U. Thomas,et al.  The Drosophila gene Serrate encodes an EGF-like transmembrane protein with a complex expression pattern in embryos and wing discs. , 1991, Development.

[5]  Geraldine Seydoux,et al.  Cell autonomy of lin-12 function in a cell fate decision in C. elegans , 1989, Cell.

[6]  R. J. Fleming,et al.  Specific EGF repeats of Notch mediate interactions with Delta and serrate: Implications for notch as a multifunctional receptor , 1991, Cell.

[7]  W. Harris,et al.  Xotch, the Xenopus homolog of Drosophila notch. , 1990, Science.

[8]  T. Schedl,et al.  Cell-cell interactions prevent a potential inductive interaction between soma and germline in C. elegans , 1990, Cell.

[9]  B. Meyer,et al.  Assessment of X chromosome dosage compensation in Caenorhabditis elegans by phenotypic analysis of lin-14. , 1987, Genetics.

[10]  G. Seydoux,et al.  Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans , 1990, Nature.

[11]  S. Artavanis-Tsakonas,et al.  Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats , 1985, Cell.

[12]  D. Baillie,et al.  Genetic analysis of a major segment [LGV(left)] of the genome of Caenorhabditis elegans. , 1991, Genetics.

[13]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Priess,et al.  Cell interactions involved in development of the bilaterally symmetrical intestinal valve cells during embryogenesis in Caenorhabditis elegans. , 1992, Development.

[15]  R. Fehon,et al.  Implications of dynamic patterns of Delta and Notch expression for cellular interactions during Drosophila development. , 1993, Development.

[16]  J. Kimble,et al.  glp-1 Is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans , 1987, Cell.

[17]  I. Greenwald,et al.  glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins , 1989, Cell.

[18]  J. Campos-Ortega,et al.  The neurogenic gene Delta of Drosophila melanogaster is expressed in neurogenic territories and encodes a putative transmembrane protein with EGF‐like repeats , 1987, The EMBO journal.

[19]  K. Fechtel,et al.  Delta, a Drosophila neurogenic gene, is transcriptionally complex and encodes a protein related to blood coagulation factors and epidermal growth factor of vertebrates. , 1988, Genes & development.

[20]  J Kimble,et al.  Two homologous regulatory genes, lin-12 and glp-1, have overlapping functions. , 1991, Development.

[21]  H. Horvitz,et al.  The lin-12 locus specifies cell fates in caenorhabditis elegans , 1983, Cell.

[22]  D. Baillie,et al.  The genetic analysis of a reciprocal translocation, eT1(III; V), in Caenorhabditis elegans. , 1981, Genetics.

[23]  Tian Xu,et al.  Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila , 1990, Cell.

[24]  S F Altschul,et al.  Protein database searches for multiple alignments. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[26]  V. Ambros,et al.  Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. , 1991, The EMBO journal.

[27]  R. J. Fleming,et al.  The gene Serrate encodes a putative EGF-like transmembrane protein essential for proper ectodermal development in Drosophila melanogaster. , 1990, Genes & development.

[28]  H. Schnabel,et al.  The glp-1 locus and cellular interactions in early C. elegans embryos , 1987, Cell.

[29]  S. Rogers,et al.  Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. , 1986, Science.

[30]  E. Appella,et al.  Structure and function of epidermal growth factor‐like regions in proteins , 1988, FEBS letters.

[31]  P. Simpson,et al.  The choice of cell fate in the epidermis of Drosophila , 1991, Cell.