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Abstract

A fundamental feature of the nervous system is its topographic organization. The motor system, for example, is topographically organized, as the position of motor neuron cell bodies in the central nervous system (CNS) correlates with which muscle targets will be innervated at the periphery. For their proper topographic organization, motor neurons must acquire their regional identity features, such as neurotransmitter receptors, signaling proteins, ion channels, etc. Many studies across model systems have focused on elucidating the transcriptional mechanisms that govern motor neuron regional identity. While much has been discovered in terms of transcription factor involvement in these mechanisms, whether and how epigenetic modifications (e.g., DNA modifications, histone modifications, chromatin modifications) control motor neuron regional identity remains poorly understood. In this thesis, we leveraged the Caenorhabditis elegans motor system to uncover a new role of a highly conserved chromatin remodeling complex (polybromo-associated BRG1-associated factor (PBAF), part of the switch/sucrose non-fermentable (SWI/SNF) family of chromatin remodelers) in motor neuron regional identity. We first show that mutant C. elegans animals lacking critical PBAF subunits display ectopic expression of the glutamate receptor glr-4/GRIK4 in ventral nerve cord motor neurons, while also displaying loss of expression of other terminal identity features (itr-1/ITPR1, avr-15/GLRA1-3, glr-5/GRIK1/3, ser-2/HTR1A) in tail motor neurons. Second, we observe that PBAF repression of glr-4/GRIK4 is cell-autonomous and occurs only in specific motor neuron subtypes. Finally, we describe another conserved transcription factor, mab-9/Tbx20, that also represses glr-4/GRIK4 in ventral nerve cord motor neurons, suggesting a model for the observed specificity of PBAF activity. That is, a sequence-specific transcription factor (MAB-9/Tbx20) may recruit PBAF to the glr-4/GRIK4 cis-regulatory region to accomplish repression. Altogether, the data in this thesis presents a novel role for the PBAF chromatin remodeler as an activator in specific motor neuron subtypes of the ventral nerve cord and a repressor in tail motor neurons, and thus as a critical regulator of motor neuron regional identity.

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