Genetic mechanisms required for the development of the CO2 chemosensory neurons of C. elegans.

摘要

ABSTRACT The nervous system comprises more diverse and intricately specialized cell types than any other tissue in the body. Understanding the developmental mechanisms that generate cellular diversity in the nervous system is a major challenge in neuroscience. The nematode C. elegans offers the opportunity to study neuronal development at the molecular level with extraordinary resolution.;My dissertation focuses on the elucidation of genetic mechanisms required for the proper development of the chemosensory BAG neurons, which are specialized for detecting the respiratory gas carbon dioxide (CO2). Analogs of these neurons play diverse roles in animals from different phyla. CO 2-sensing neurons in the mammalian brainstem are critical regulators of the respiratory motor program, and their dysfunction has been linked to fatal apneas such as Sudden Infant Death Syndrome. In nematodes, CO2-sensing neurons mediate an avoidance behavior, but their ethological function was not known.;In my initial studies of BAG neuron development, I demonstrated that a conserved ETS-family transcription factor directly regulates genes required for CO2-sensing, including the receptor-type guanylate cyclase, GCY-9, which likely functions as a CO2 receptor. To uncover other genes that function together with ets-5, I carried out a large-scale chemical mutagenesis screen for mutants with improper BAG neuron differentiation. From this screen I identified two new genes required for BAG neuron development: the Pax6 homolog vab-3 and the p38 Mitogen-Activated Protein (MAP) kinase pmk-3.;VAB-3 likely acts during embryonic development to pattern the expression of ETS-5 in head neurons of C. elegans. In loss of function vab-3 mutants, ETS-5 protein is misexpressed in hypodermal cells and a motor neuron, in addition to its expression in BAG. VAB-3 likely represses transcription of ETS-5 in some lineages, such as those that give rise to hypodermal cells.;I next demonstrated that the p38 MAPK PMK-3 functions in a Toll-like receptor (TLR) signaling pathway. This discovery revealed an unexpected role for TLR signaling in neuronal differentiation. Because TLR signaling was known to be required for behavioral responses to microbes, I tested whether BAG neurons were required for pathogen avoidance. I found that this was the case and propose that TLR signaling functions in pathogen avoidance by promoting the development and function of chemosensory neurons that surveil the metabolic activity of environmental microbes.;Because ETS-5, VAB-3 and TOL-1 are members of gene families that are conserved between nematodes and vertebrates, a similar mechanism might act in the specification and differentiation of CO2-sensing neurons in other phyla.