The long-term goal is to understand the patterning and differentiation of specialized cell types and their assembly into functional organs. We wish to understand how genes interact to give tissue specialization, including: 1) The mechanisms by which a broadly used receptor can confer a tissue specific response; 2) The molecular basis of terminal differentiation; and 3) The mechanisms by which the development of two tissues is coordinated during their connection. The nematode C. elegans is used as a model organism because these questions can be studied at the resolution of single cells. We are focusing on a subset of uterine cells. Development of the two uterine cell types (called utse and uv1) that connect to the vulva and the intermediate precursor cell (called pi) that produces them involves strategies used broadly in the formation of many tissues: induction, pattern formation, and a reciprocal cell-cell interaction. A major goal is to understand how these processes are integrated during development to reproducibly produce correctly patterned and differentiated cells that always connect to the same cells of the adjacent tissue. Using a genetic screen, we have identified genes required for 1) pi cell induction, and 2) differentiation of the utse and its connection to the vulva; we now propose to undertake a developmental and molecular genetic analysis. The lin-12 gene, a member of the Notch family of receptors, mediates lateral inhibition during several instances of C. elegans development, but induction only during ventral uterine development (in specification of the pi fate). This project involves molecular analysis of three genes required for pi fate specification but not for other lin-12-mediated decisions. These genes may contribute to the cell-specific response of pi cells to lin-12 activity. Activating mutations in human and mouse Notch genes cause cancer in some cell types but not others; thus, understanding the molecular basis of the cell type specific behavior of the receptor family may have important implications for delineating the genetic basis of cancer. The C. elegans presenilin sel-12 is needed uniquely for pi cell induction but redundantly with hop-1 for other lin-12-mediated decisions. By studying how sel-12 functions in the pi cell induction pathway, we hope to provide insight into how the presenilin family of genes, which can predispose individuals to Alzheimer s disease, function in Notch signaling pathways in development.
