We are interested in the molecular mechanisms by which embryonic cells stop dividing and assume particular differentiated fates, and are studying this problem in the nematode C. elegans. In normal development both of the first two embryonic cells, called the AB blastomere and the PI blastomere, produce muscles of the pharynx. Although PI produces these cell types autonomously, AB is induced to produce pharyngeal muscles. We want to understand the molecular basis for this inductive event. Several maternally-expressed genes, including glp-1, aph-1, aph-2, pop-1, and mex- 3, are essential for normal pharyngeal development. The glp-1 gene encodes a homolog of the C. elegans gene lin-12 and the Drosophila gene Notch, a family of proteins that now appear to be key regulators of cell-cell interactions in a wide variety of animals. Genes homologous to glp-1 recently have been identified in humans, and aberrant forms of these molecules have been implicated in certain malignancies. Very little is understood about how cell-cell interactions determine cell fate, however the early inductive interaction in the C. elegans embryo is almost ideal for such a study. First, there are only 4 blastomeres in the embryo when the inductive interaction begins. Second, it is possible to dissociate and rejoin wild type or mutant blastomeres at this stage. Finally, the genetics available in C. elegans provides an extremely powerful tool for uncovering genes involved in the inductive interaction. Some of the genes that determine the fate of the inducing cell already have been identified, and one of these (the skn-1 gene) appears to encode a novel, nuclear localized transcription factor. We propose a phenotypic/molecular analysis of the aph-1, aph-2, pop-1, and mex-3 genes which were identified by genetic screens during the previous years of this grant. Knowing the molecular nature and cellular locations of the corresponding gene products should provide a great deal of insight into the nature of cell-cell interactions.
