? ? The mesodermal germ layer gives rise to a variety of functionally important cell types, including different muscle and non-muscle cells. Elucidating how different mesodermal cell fates are specified is not only important to the understanding of early stages of animal development, but will also guide investigations into the molecular basis of various cancers and genetic diseases that specifically affect mesodermally derived cell types. The long-term goal of this proposal is to understand the mechanisms required for mesodermal cell fate specification and diversification using the C. elegans postembryonic mesodermal lineage, the M lineage, as a model system. The M lineage is derived from a single precursor cell and produces a number of different muscle and non- muscle cell types. A number of key factors and pathways involved in M lineage fate specification have been identified, including SMA-9, the sole C. elegans homolog of the Drosophila and vertebrate Schnurri (SHN) proteins. Our analysis on SMA-9 function suggests that SMA-9 specifically antagonizes TGF_ signaling in the M lineage. Interestingly, SMA-9 also regulates body size, but by playing a contributory role in the TGF_ pathway. Thus SMA-9 exerts context-dependent activities in modulating the TGF_ pathway. In this proposal, Specific aims 1 and 2 are designed to identify SMA-9 cofactors and downstream targets that are mediating these context-dependent activities.
Specific aim 3 is designed to determine the functions of three genes that are mediating binary fate decisions in the M lineage. Not only are these genes potential SMA-9 targets, but determining how they function in the M lineage may also reveal additional molecular mechanisms in mesodermal patterning and cell fate specification. Together results from the proposed studies will expand our current understanding of how a complex lineage is built.7. ? ? Public Health Relevance: The mesodermal germ layer gives rise to a variety of functionally important cell types, including different muscle and non-muscle cells. Elucidating how different mesodermal cell fates are specified is not only important to the understanding of early stages of animal development, but will also guide investigations into the molecular basis of various cancers and genetic diseases that specifically affect mesodermally derived cell types. ? ? ?
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