Regulatory Architecture of Glia Cell Type Diversity in C. Elegans

PROJECT SUMMARY The nervous system of most bilaterian animals consists of two classes of cells, neurons and glia, each of which comprised of many different types. While great strides have been made in understanding the gene regulatory mechanisms that specify the fate and identity of distinct neuronal cell types, comparatively little is known about how glia cell types differentiate into distinct types and subtypes and how their differentiated state is maintained throughout the life of the animal. The restricted size and complexity of the nervous system of C. elegans has enabled the discovery of broad, overarching organizational themes of neuronal cell fate specification. Specifically, we have recently described that all neuronal cell types of the worm are uniquely defined by neuron type-specific combinations of homeodomain protein expression and, consequently, that the vast majority, if not all, neuronal cell types require homeodomain proteins for their proper identity fate specification. Moreover, most homeodomain proteins work as master-regulatory terminal selectors to coregulate the many distinct identity features of a given neuron types. In this grant proposal, we set out to test the hypothesis that similar gene regulatory principles operate to specify the identity and diversity of the complete set of 17 distinct glial cell types in C. elegans. Leveraging the unique opportunities offered by the C. elegans model system, we ask whether each of the 17 distinct glial cell types of the C. elegans hermaphrodite is uniquely defined by a glial-type specific signatures of homeodomain proteins. Using rigorous loss of function analysis, in combination with gain of function analysis, we will ask whether homeodomain proteins operate in a master regulatory-type manner to specify the fate of all the distinct glial cell type of C. elegans. Lastly, we will integrate the function of homeodomain proteins with potential pan-glia regulators of glial fate specification. This approach presents the first nervous system-wide view of glia cell fate specification, potentially carving out general regulatory principles about glial identity specification and maintenance. Our analysis may provide insights into potential evolutionary trajectories of glial cell type specification and may reveal candidates for future functional analysis in the vertebrate system.