Dissecting the Development and Function of C. elegans Glia with Mutations of the mls-2 and vab-3 Genes

The past decade has produced much evidence that glia, the major cellular component of vertebrate nervous systems, play active integral roles in a variety of processes including neuronal migration, synaptogenesis, and modulation of synaptic activity. Yet, many aspects of glia-neuron interactions remain obscure partly because manipulation of glia can result in neuronal death, hampering attempts to study glial cells in vivo. Moreover, a comprehensive understanding of glia differentiation is not yet achieved, although several key molecules in the process have been discovered. C. elegans possesses glia-like cells that are morphologically reminiscent of vertebrate glia. In this thesis, I show that C. elegans CEPsh glia possess molecular and functional similarities to vertebrate glia. I identify transcriptional programs specifying these glia, demonstrating ventral- and dorsal-restricted roles for the mls-2/Nkx/Hmx and vab-3/Pax6/Pax7 genes, respectively, in differentiation and expression of the genes hlh-17/Olig and ptr-10/Patched-related. Similar pathways regulate oligodendrocyte generation in vertebrate spinal cords. Using mls-2 and vab-3 mutants, as well as CEPsh glia-ablated animals, I also uncover roles for CEPsh glia in dendrite extension and axon branching and guidance, and show that these latter functions are mediated, at least in part, by the UNC-6/Netrin protein. During the course of this study, I also confirmed that C. elegans CEPsh glia are not required for neuronal survival. Overall, the conservation of molecular features between the development of C. elegans CEPsh glia and vertebrate oligodendrocytes, together with the lack of neurotrophic roles for these glia, suggests that C. elegans can serve as a unique model organism to explore, in vivo, basic aspects of metazoan glia development and function, as well as glia-neuron interactions