The mesodermal germ layer gives rise to a variety of functionally important cell types, including striated and non-striated muscles as well as non-muscle cells. Understanding the regulatory mechanisms underlying mesoderm diversification has widespread implications in basic biology, stem cell biology and clinical research. The C. elegans postembryonic mesodermal lineage, the M lineage, provides unique advantages for studying mesoderm diversification at single cell resolution. The M lineage is derived from a single pluripotent precursor cell, the M mesoblast, which during hermaphrodite postembryonic development proliferates and produces six cell types: striated bodywall muscles (BWM), non-muscle coelomocytes (CC), and four classes of non-striated sex muscles. Both M and its descendants divide in a reproducible pattern, which is under both developmental and cell cycle control. The M lineage is thus ideally suited to investigating how different mesodermal fates are diversified from a single progenitor cell, how positional information is integrated with lineage-intrinsic information, and how diverse programs of asymmetric patterning, cell division timing and orientation, and cell fate specification are integrated. Our long-term goal is to understand the regulatory logic of M lineage diversification in mechanistic detail. During the previous and current funding periods, we have successfully conducted in-depth molecular genetic studies on signaling and transcriptional regulatory mechanisms involved in M lineage development. Our results have allowed us to begin to assemble the regulatory networks involved in the proper specification of BWM, CC and the precursor of the non-striated muscles, the sex myoblast (SM). Our identification and characterization of several transcription factors involved in these fate specification processes have also provided key insights into how these factors may function in similar processes in vertebrates and how their malfunction may be linked to certain human diseases. More importantly, these studies have provided us with reagents and exciting opportunities to address additional fundamental questions in developmental biology. In this proposal, we will exploit the M lineage to dissect mechanisms involved in the specification and proliferation of multi-potent progenitors (Aim 1) and mechanisms underlying the specification of different types of non- striated/smooth muscles (Aim 2). Because many of the factors that we have identified are conserved in vertebrates and our studies of them in the M lineage have contributed to the mechanistic understanding of their functions in general, we propose to molecularly identify and characterize two "new" factors critical for M lineage development (Aim 3). Finally, we are at the point to exploit the M lineage to dissect the connection between cell type- and stage-specific chromatin features and transcription factor action during cell fate specification and cell differentiation in vivo, an important area in developmental biology that we know very little about. We propose to address this question using the newly developed INTACT (isolation of nuclei tagged in specific cell types) method (Aim 4).
The mesodermal germ layer gives rise to a variety of functionally important cell types, including striated and non-striated muscles as well as non-muscle cells. Understanding the regulatory mechanisms underlying mesoderm diversification has widespread implications in basic biology, stem cell biology and clinical research.
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