The goal of this research is to elucidate the molecular processes that direct blastomere differentiation and formation of embryonic germ layers and organs. The endoderm, or innermost germ layer, in C. elegans arises from a clonal progenitor, the E blastomere, which produces exclusively the intestine. end-1 and -3, which encode apparent GATA transcription factors, and end-2, encoding a nuclear hormone receptor family member, reside in a genomic region (the """"""""EDR"""""""") essential zygotically to specify endoderm. These """"""""end"""""""" genes appear to act redundantly and are the only zygotic genes known to regulate founder cell or germ layer identity. They are apparently regulated by both a maternally encoded Wnt-type signaling pathway and the maternal SKN-1 transcription factor, which collaborate to specify endoderm. The end genes provide the opportunity to explore how maternal Wnt signaling and SKN-1 are linked to regulatory events leading to formation of a germ layer. Other genes, including hnl-1, eel-1, elt-2, zygotic skn-1, and pha-4 encode apparent transcription factors expressed E lineage that appear to be phylogenetically conserved downstream regulators of endoderm formation. Among the hypotheses tested are that the end genes are direct targets of maternal SKN-1 and the Wnt pathway, that different regulators act on overlapping sets of target genes, that the end genes control the identity of E while their targets control specific differentiation events, and that the end genes regulate the expression of a large battery of genes involved in diverse processes including gastrulation, differentiation, and organogenesis. The major goals are to: a) characterize the function and regulation of the end genes, hnl-1 and eel-1, b) analyze the interrelation between the end genes and five downstream genes that are probable components of a conserved regulatory network specifying endoderm, c) examine how EDR genes can determine which of three founder cell identities and germ layers the E cell can engender and identify genes that influence this decision, d) investigate how different GATA factors specify distinct cell fates, e) reveal how Wnt signaling and SKN-1 converge on end-1 regulation to promote endoderm formation and identify other regulators of end-1, and f) identify genes that are differentially expressed in the endoderm and which may execute various aspects of endoderm formation. These studies will illuminate how germ layers and organs are formed, processes disrupted in many human birth defects. Moreover, they will examine how dividing cells select unique pathways of differentiation, thereby helping to understand how normal controls of proliferation and differentiation are altered in cancers.
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