Egg to Embryo: Gene Regulatory Circuitry in Development

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This is an application for continuation and broadening of a Program Project now in its 9* year. Here we propose to build in many directions on the large success we have had in solving and authenticating a gene regulatory network (GRN) for development. GRNs provide causal explanations for developmental processes in the terms of the genomic regulatory code, where all species-specific developmental processes are ultimately programmed. A developmental GRN serves as a conceptual, system-level logic map, of direct predictive power. Thus GRNs bridge between functional genomic DNA sequence of regulatory significance and the biology of embryogenesis and body plan formation. They do this by specifying the regulatory interactions which causally drive the progression of regulatory states in diverse cellular territories. During recent years, this Program has been responsible for the experimental solution of the most advanced developmental GRN yet available for any developing animal organism. This is the GRN underlying the specification of the endomesodermal territories of the sea urchin embryo. Recently proof of the principle that as a GRN approaches completion it indeed provides explanation of all the observed biological functions has been obtained in this work. We now intend to capitalize on the growing suite of successful technological approaches to GRN analysis that we have developed, to confront challenges that heretofore were inaccessible, or could not even have been defined. The current sea urchin embryo GRN concerns about half of the embryo, that ultimately forming the gut, the skeletogenic cell lineages and the non-skeletogenic mesoderm, from the earliest zygotic genomic activity (at the beginning of cleavage) to just before gastrulation. A start on the oral and aboral ectodermal GRNs has also been made. We intend to expand this GRN in qualitatively distinct ways which will represent radical advances if successful. In the DAVIDSON COMPONENT the GRN will be expanded to include all regulatory genes predicted by genomic analysis, and observed to be expressed specifically in the endomesodermal territories, (cont.)