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Investigation of the Role for Terminal Schwann Cells in Neuromuscular Junction Development and Disease
AdvisorGould, Thomas W
Biochemistry and Molecular Biology
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The studies performed in this thesis investigate the roles of Schwann cells (SCs) in the development of the peripheral nervous system and in an inherited peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease. Schwann cells are an integral aspect of the peripheral nervous system and play a large variety of roles to support, maintain, and modulate this system. The experiments performed in this thesis investigated how SCs regulate the development of the neuromuscular junction (NMJ) and maintain early derived NMJs into adulthood. Differentiation of SCs results in two main subtypes, myelinating or nonmyelinating. The axonal-derived myelinating Schwann cells are essential for the protection, support, and function of motor axons. Axonal-derived nonmyelinating SCs encompass sensory or autonomic nerve bundles and provide structural support to these peripheral nerve subtypes. Nonmyelinating SCs are also found at the motor terminus and are thus known as terminal SCs (TSCs). TSCs are in close proximity with the presynaptic motor nerve and postsynaptic receptor making up the third component of the tripartite synapse. The localization of these cells enables them to directly affect and regulate NMJ survival and function.Using a murine model deficient in all SC subtypes, the homozygote erbB3 (erbB3-/-) model, we have demonstrated the necessity of SCs for NMJ maintenance and viability. However, this model does not allow for the discrimination of roles specific to either axonal SCs or TSCs. We thus applied a unique methodology to isolate the transcriptomes of axonal SCs and TSCs for subsequent RNA sequencing experiments. Analysis of RNA sequencing data revealed 13 and 9 candidate genetic markers specific to TSCs and axonal SCs, respectively. Finally, we developed novel confocal imaging analysis combined with electron microscopy and electrophysiological methods to examine NMJ deficits in CMT type 1A (CMT1A). CMT1A is the most common form of CMT and is due to a mutation in the peripheral myelin protein 22 gene, thus affecting SCs. This multifaceted approach allowed us to perform a thorough investigation of the functional and anatomical defects of NMJs in the homozygote Trembler-J mouse. We found that these mice exhibited symptomology and pathology characteristic of severe hypomyelination despite normal innervation patterns of the NMJ. Deficits in both structure and function of the NMJ were observed implicating both axonal SCs and TSCs involvement in CMT1A.