Searle Scholar Profile : Iva S. Greenwald (1987)

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	Iva S. Greenwald Professor Department of Biochemistry Columbia University 701 West 168th Street/HHSC 720A New York, NY 10032 Voice: 212/305-6928 or -6931 Fax: 212/740-2719 E-mail: greenwald@cuccfa.ccc.columbia.edu Personal Homepage 1987 Searle Scholar

Cell Specification During Development

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 the laboratory involve the study of the lin-12 gene. LIN-12 is the archetype of the LIN-12/Notch family of putative transmembrane proteins that is found throughout 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 Êhave 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 strategies 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 proteins functioning in the signal transduction mechanism. We have identified a number of sel genes, which may interact directly or indirectly with lin-12 , by mutations that s uppress and/or e nhance l in-12 mutations. In addition, we have screened directly for proteins that interact with defined regions of the LIN-12 protein. A combination of genetic and molecular characterization of candidate genes is elucidating their role in lin-12 -mediated cell signalling.

Our interest in one sel gene, sel-12 , extends beyond its involvement in lin-12 -mediated signalling. 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 .