The mesodermal germ layer gives rise to a variety of functionally important cell types, including different 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. Genetic analysis has identified one key regulator in M lineage fate specification, sma-9, which encodes the single C. elegans ortholog of the Drosophila protein Schnurri (SHN). SNH has only been previously implicated in the TGF-B pathway. Analysis of SMA-9 function in the M lineage has uncovered a novel role for SMA-9 in mediating lineage specific LIN-12/Notch signaling. The experiments described in the first two specific aims will further characterize the function of SMA-9 including its interaction with LIN-12/Notch signaling and will identify factors/pathways that function together with SMA-9. These studies will help elucidate how the important SMA-9/SHN family of proteins contributes to the molecular mechanisms regulating signaling specificity at different cellular contexts.
Specific aim 3 proposes experiments to further characterize mutations in a number of loci not previously known to function in M lineage cell fate specification. Uncovering the molecular identity and function of these genes may lead to identification of additional novel molecular mechanisms in cell fate specification, and will expand our current understanding of how a complex lineage is built. The studies proposed in these three specific aims may be of further value in understanding human craniofacial disorders, since mutations in the human homologs of several C. elegans factors functioning in the M lineage cause such syndromes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cell Development and Function Integrated Review Group (CDF)
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Greenberg, Judith H
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Cornell University
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Shen, Qinfang; Toulabi, Leila B; Shi, Herong et al. (2018) The forkhead transcription factor UNC-130/FOXD integrates both BMP and Notch signaling to regulate dorsoventral patterning of the C. elegans postembryonic mesoderm. Dev Biol 433:75-83
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