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Gene Review

lin-12  -  Protein LIN-12

Caenorhabditis elegans

 
 
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High impact information on lin-12

  • In addition, lin-12 activity promotes expression of lin-12 and represses expression of lag-2 [1].
  • 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 [1].
  • Our results also suggest that equivalent truncated forms of lin-12/Notch family members in vertebrates, including known oncogenes, are similarly active [2].
  • In one model, we propose that the AC sends an intercellular signal intended to interact with the lin-12 product in somatic gonadal cells; when lin-12 activity is absent, the signal interacts instead with the related glp-1 product in germline [3].
  • We have identified two conditions under which a proximal somatic cell, the anchor cell (AC), inappropriately maintains proximal germline nuclei in mitosis: when defined somatic gonadal cells have been ablated in wild type, and in lin-12 null mutants [3].
 

Biological context of lin-12

  • lin-12, a nematode homeotic gene, is homologous to a set of mammalian proteins that includes epidermal growth factor [4].
  • Gene dosage studies suggest that a high level of lin-12 activity specifies one cell fate and a low level specifies an alternative fate [5].
  • By correlating the fates of Z1.ppp and Z4.aaa with the lin-12 genotype of nearly every cell in these mosaics, we conclude that lin-12 function is VU cell autonomous [6].
  • Genetic studies indicate that the lin-12 and glp-1 proteins act as receptors in specific developmental cell interactions and that their functions are partially redundant. lin-12 glp-1 double mutants display certain embryonic defects not found in either single mutant [7].
  • We report here the complete DNA sequence of lin-12: 13.5 kilobases (kb) derived from genomic clones and 4.5 kb from complementary DNA clones [8].
 

Anatomical context of lin-12

  • By contrast, lin-12 mediates somatic cell interactions, including those between the precursor cells that form the vulval hypodermis (VPCs) [9].
  • 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 [10].
  • SEL-2, the C. elegans neurobeachin/LRBA homolog, is a negative regulator of lin-12/Notch activity and affects endosomal traffic in polarized epithelial cells [11].
  • In the uterus, lin-29 functioned upstream of lin-12 in the induction of pi cells and was necessary to maintain expression in the AC of lag-2, which encodes a ligand for LIN-12 [12].
  • Both weak and strong sel-12 mutations cause defects in the sex muscles that resemble the defects we found in lin-12 hypomorphic alleles, suggesting a previously uncharacterised LIN-12 signalling event late in postembryonic mesoderm development [13].
 

Associations of lin-12 with chemical compounds

 

Physical interactions of lin-12

 

Regulatory relationships of lin-12

  • Unexpectedly, we find that glp-1 RNA is also expressed in larval somatic tissues and that lin-12 RNA is abundant in early embryos [17].
  • Reducing sel-12 activity can suppress the effects of elevated lin-12 activity when LIN-12 is activated by missense mutations but not when LIN-12 is activated by removal of the extracellular and transmembrane domains [18].
 

Other interactions of lin-12

 

Analytical, diagnostic and therapeutic context of lin-12

  • Here, we report the molecular lesions associated with lin-12 gain-of-function mutations, cell isolation experiments, and genetic studies of an unusual lin-12 allele [24].

References

  1. Reciprocal changes in expression of the receptor lin-12 and its ligand lag-2 prior to commitment in a C. elegans cell fate decision. Wilkinson, H.A., Fitzgerald, K., Greenwald, I. Cell (1994) [Pubmed]
  2. Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo. Struhl, G., Fitzgerald, K., Greenwald, I. Cell (1993) [Pubmed]
  3. Cell-cell interactions prevent a potential inductive interaction between soma and germline in C. elegans. Seydoux, G., Schedl, T., Greenwald, I. Cell (1990) [Pubmed]
  4. lin-12, a nematode homeotic gene, is homologous to a set of mammalian proteins that includes epidermal growth factor. Greenwald, I. Cell (1985) [Pubmed]
  5. The lin-12 locus specifies cell fates in Caenorhabditis elegans. Greenwald, I.S., Sternberg, P.W., Horvitz, H.R. Cell (1983) [Pubmed]
  6. Cell autonomy of lin-12 function in a cell fate decision in C. elegans. Seydoux, G., Greenwald, I. Cell (1989) [Pubmed]
  7. Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila. Tax, F.E., Yeargers, J.J., Thomas, J.H. Nature (1994) [Pubmed]
  8. The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch. Yochem, J., Weston, K., Greenwald, I. Nature (1988) [Pubmed]
  9. Carboxy-terminal truncation activates glp-1 protein to specify vulval fates in Caenorhabditis elegans. Mango, S.E., Maine, E.M., Kimble, J. Nature (1991) [Pubmed]
  10. lin-12 and glp-1 are required zygotically for early embryonic cellular interactions and are regulated by maternal GLP-1 signaling in Caenorhabditis elegans. Moskowitz, I.P., Rothman, J.H. Development (1996) [Pubmed]
  11. SEL-2, the C. elegans neurobeachin/LRBA homolog, is a negative regulator of lin-12/Notch activity and affects endosomal traffic in polarized epithelial cells. de Souza, N., Vallier, L.G., Fares, H., Greenwald, I. Development (2007) [Pubmed]
  12. The Caenorhabditis elegans heterochronic gene lin-29 coordinates the vulval-uterine-epidermal connections. Newman, A.P., Inoue, T., Wang, M., Sternberg, P.W. Curr. Biol. (2000) [Pubmed]
  13. The Caenorhabditis elegans presenilin sel-12 is required for mesodermal patterning and muscle function. Eimer, S., Donhauser, R., Baumeister, R. Dev. Biol. (2002) [Pubmed]
  14. SEL-5, a serine/threonine kinase that facilitates lin-12 activity in Caenorhabditis elegans. Fares, H., Greenwald, I. Genetics (1999) [Pubmed]
  15. Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased A beta42 secretion in mammalian cells but impaired Notch/lin-12 signalling in C. elegans. Zhang, D.M., Levitan, D., Yu, G., Nishimura, M., Chen, F., Tandon, A., Kawarai, T., Arawaka, S., Supala, A., Song, Y.Q., Rogaeva, E., Liang, Y., Holmes, E., Milman, P., Sato, C., Zhang, L., St George-Hyslop, P. Neuroreport (2000) [Pubmed]
  16. Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans. Sundaram, M., Greenwald, I. Genetics (1993) [Pubmed]
  17. Transcript analysis of glp-1 and lin-12, homologous genes required for cell interactions during development of C. elegans. Austin, J., Kimble, J. Cell (1989) [Pubmed]
  18. Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans. Levitan, D., Greenwald, I. Development (1998) [Pubmed]
  19. Identification and characterization of genes that interact with lin-12 in Caenorhabditis elegans. Tax, F.E., Thomas, J.H., Ferguson, E.L., Horvitz, H.R. Genetics (1997) [Pubmed]
  20. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. Oberg, C., Li, J., Pauley, A., Wolf, E., Gurney, M., Lendahl, U. J. Biol. Chem. (2001) [Pubmed]
  21. sel-7, a positive regulator of lin-12 activity, encodes a novel nuclear protein in Caenorhabditis elegans. Chen, J., Li, X., Greenwald, I. Genetics (2004) [Pubmed]
  22. p24 proteins and quality control of LIN-12 and GLP-1 trafficking in Caenorhabditis elegans. Wen, C., Greenwald, I. J. Cell Biol. (1999) [Pubmed]
  23. The Caenorhabditis elegans sel-1 gene, a negative regulator of lin-12 and glp-1, encodes a predicted extracellular protein. Grant, B., Greenwald, I. Genetics (1996) [Pubmed]
  24. Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans. Greenwald, I., Seydoux, G. Nature (1990) [Pubmed]
 
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