During C.elegans development, cell-cell interactions influence several different binary decisions between alternative cell fates. The lin-12 gene appears to mediate certain cell-cell interactions that specify cell fates, perhaps by serving as a receptor for intercellular signals. lin-12 is the archetype of the """"""""lin-12/Notch gene family"""""""" of putative transmembrane proteins that is ubiquitous throughout the animal kingdom; notable structural features include a putative transmembrane domain, the presence of repeated epidermal growth factor (EGF)-like motifs the putative extracellular region, and the presence of repeated """"""""cdc 10/SW16"""""""" motifs in the putative intracellular region. In man, a member of the lin-12/Notch gene family has been associated with translocation breakpoints in certain childhood lymphoblastic leukemias. Our ultimate goal is to understand at the biochemical level how lin-12 specifies cell fates. In this grant, we propose to study the expression and distribution of the lin-12 mRNA and protein products, identify the sequences necessary for correct lin-12 mRNA expression, determine the consequences of ectopic expression of lin-12, study the relationship between lin-12 structure and function, investigate the role of lin-12 in particular cell fate decisions and identify genes that interact with lin- 12. The ubiquity of intercellular communication in cell fate choice and of genes like lin-12, combined with the special attributes of C.elegans as a genetic system, make the work described in this proposal of general significance to the field of developmental biology. There is also a potential health-relatedness: human diseases such as cancer are manifestations of what are essentially abnormal cell fate choices. Understanding how normal cell fate choices are made is bound to provide insight into abnormal cell fate choices. The finding that certain human T cell leukemias are associated with breakpoints in a lin-12/Notch family member strengthens our conviction on this point.
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