Mesoderm Specification in C. elegans

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A central problem in developmental biology is to account for how tissue and cell type diversity arises during embryonic development in the generation of the three fundamental germ layers in animals (endoderm, mesoderm and ectoderm). The nematode, C. elegans, has been an excellent model system in which to explore mechanisms of cell fate specification and to elucidate the molecular players involved. In early mbryogenesis, the C. elegans mesendodermal precursor EMS is specified by the activation of the GATA-like transcription factors MED-1 and -2. The MEDs function with the conserved Wnt signaling pathway to specify either mesoderm (MS) or endoderm (E) fate in the EMS daughter cells. While much is known about endoderm, very little is known about how the more complex mesoderm lineage is specified. The laboratory of Dr. Maduro is interested in elucidating the mesodermal regulatory gene network and understanding how the Wnt pathway restricts activation of MED target genes to the MS cell. They have determined the novel binding site of MED-1 and used this site to identify 19 new candidate target genes, many of which have been confirmed to be expressed in mesoderm or endoderm. This proposal aims to characterize these target genes and study their regulation by MED-1 and the Wnt pathway. First, they will complete the expression analysis of the candidate MED-1 targets, and with emphasis on the predicted transcription factors, their developmental roles will be assessed genetically. Second, they will analyze the structure-function properties of MED-1 to learn more about how this novel regulator functions in mesoderm specification. Third, they will characterize the basis for differential mesodermal vs. endodermal activation of MED target genes that are regulated through an apparently novel Wnt-based mechanism. As homologs of candidate MED target genes function in mesoderm in other systems, and as the Wnt pathway functions in developmentally important processes throughout metazoa (including cancer in humans), this work promises to reveal new principles about early embryonic development and gene regulation that are widely applicable.Broader impacts: This is the first grant for a beginning investigator of Hispanic descent. The work proposed will be central to the research training of two female PhD candidates at UC Riverside (UCR). Undergraduates drawn from UCR's ethnically-diverse student body will participate in the project. Dr. Maduro will integrate education and research by teaching graduate and undergraduate courses in developmental biology.