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One of the fundamental problems in developmental biology is how so many different cell types are generated from a one-cell zygote. It is known that cell-cell interactions play important roles in cell type specification during development. We study this process in the nematode C. elegans, which is extremely tractable to genetic and molecular manipulation. However, since the mechanisms and molecules involved in cell fate specification appear to be conserved in mammals, studies in simpler organisms such as C. elegans have direct application to higher animals.

Many projects in my laboratory involve the study of lin-12 gene. LIN-12 is the archetype of the LIN-12/Notch family of putative transmembrane proteins that is found throught the animal kingdom. In C. elegans, LIN-12 appears to function as a receptor during cell-cell interactions that specify cell fate. In mammals, genes related to lin-12 are important for normal development; furthermore, mutations in genes related to lin-12 have been associated with cancer in mice and people. Ultimately, we want to understand the molecular mechanism by which lin-12 and its relatives in higher organisms specify cell fates. We have adopted a number of stategies to achieve this goal. One strategy is a "genetics in reverse" approach. This strategy has included performing structure/function analyses of lin-12 and its ligands by using homologous and heterologous regulatory sequences to direct expression of mutant proteins in C. elegans. Another strategy is to identify other genes that influence lin-12 activity. We have identified a number of sel genes, which may interact directly or indirectly with lin-12, by mutations that suppress and/or enhance lin-12 mutations. In addition, we have screened directly for proteins that interact with defined regions of LIN-12 protein. A combination of genetic and molecular characterization of candidate genes is elucidating their role in lin-12-mediated cell signaling.

Our interest in one sel gene, sel-12, extends beyond its involvement in lin-12-mediated signaling. The SEL-12 protein is highly similar to human presenilins, which have been implicated in the development of Alzheimer's disease. The ability to bring the powerful tools of classical and molecular genetic studies in C.elegans can now be brought to bear on fundamental issues of the structure and function of the presenilins, using the same strategies as we have used for studying lin-12.

Selected Publications

Doyle, T. G., Wen, C. and Greenwald, I. (2000) SEL-8, a novel nuclear protein required for LIN-12 and GLP-1 signalling in Caenorhabditis elegans. Proc. Natl. Acad. Sci. (USA) 97, 7877-7881.

Melendez, A. and Greenwald, I. (2000) C. elegans lin-13, a member of the LIN-35 Rb class of genes involved in vulval development, encodes a protein with zinc fingers and an LXCXE motif. Genetics 155, 1127-1137.

Wen, C., Levitan, D., Li, X. and Greenwald, I. (2000) spr-2, a suppressor of the egg-laying defect caused by loss of sel-12 presenilin in Caenorhabditis elegans, is a member of the SET protein subfamily. Proc. Natl. Acad. Sci. (USA) 97, 14524-14529.

Struhl, G. and Greenwald, I. (2001) Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila. Proc. Natl. Acad. Sci. (USA) 98, 229-234.

Fares, H. and Greenwald, I. (2001) Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homologue. Nature Genet. 28, 64-68.

Fares, H. and Greenwald, I. (2001) Genetic Analysis of Endocytosis in Caenorhabditis elegans: coelomocyte uptake defective (cup) mutants. Genetics, in press.