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.
|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|
|Shen, Qinfang; Shi, Herong; Tian, Chenxi et al. (2017) The C. elegans Spalt-like protein SEM-4 functions through the SoxC transcription factor SEM-2 to promote a proliferative blast cell fate in the postembryonic mesoderm. Dev Biol 429:335-342|
|Wang, Lin; Liu, Zhiyu; Shi, Herong et al. (2017) Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with the ADAM10 Metalloprotease SUP-17 to Promote BMP Signaling in Caenorhabditis elegans. PLoS Genet 13:e1006568|
|Liu, Zhiyu; Shi, Herong; Szymczak, Lindsey C et al. (2015) Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids. PLoS Genet 11:e1005221|
|Hale, Jared J; Amin, Nirav M; George, Carolyn et al. (2014) A role of the LIN-12/Notch signaling pathway in diversifying the non-striated egg-laying muscles in C. elegans. Dev Biol 389:137-48|
|Tian, Chenxi; Liu, Jun (2013) Repulsive guidance molecules (RGMs) and neogenin in bone morphogenetic protein (BMP) signaling. Mol Reprod Dev 80:700-17|
|Tian, Chenxi; Shi, Herong; Xiong, Shan et al. (2013) The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans. Development 140:4070-80|
|Krause, Michael; Liu, Jun (2012) Somatic muscle specification during embryonic and post-embryonic development in the nematode C. elegans. Wiley Interdiscip Rev Dev Biol 1:203-14|
|Barkan, Rachel; Zahand, Adam J; Sharabi, Kfir et al. (2012) Ce-emerin and LEM-2: essential roles in Caenorhabditis elegans development, muscle function, and mitosis. Mol Biol Cell 23:543-52|
|Tian, Chenxi; Shi, Herong; Colledge, Clark et al. (2011) The C. elegans SoxC protein SEM-2 opposes differentiation factors to promote a proliferative blast cell fate in the postembryonic mesoderm. Development 138:1033-43|
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