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Title: Characterisation of the gene PTPRS in the development of the cerebral cortex
Author: Sherlock, W. T.
ISNI:       0000 0004 8499 2907
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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The cerebral cortex is a 6 layered structure, which is responsible for carrying out many of the higher functions of the brain including complex cognitive, sensory, emotional and motor tasks. During embryonic development, neuroepithelial stem cells (NSCs) or radial glia divide to produce post-mitotic neurons, which migrate radially to form the layers of the CP. We have previously shown that production of nitric oxide (NO) by neuronal nitric oxide synthase (nNOS) leads to S-nitrosylation of histone deacetylase 2 (HDAC2), thereby regulating the transcription of genes required for radial migration and cortical development. One such gene is protein tyrosine phosphatase receptor sigma (PTPRS), a membrane bound phosphatase, which acts as a receptor for chondroitin sulfate proteoglycans (CSPGs) and is associated with gross defects of several structures in the brain. Here, I have examined the role S-nitrosylation of HDAC2 in regulating the expression of PTPRS and investigated the importance of PTPRS in the developing cortex. The expression of a HDAC2 construct which cannot be nitrosylated leads to downregulation of PTPRS in neurons and PTPRS is repressed in the cortices of nNOS knockout mice. To understand how PTPRS is involved in cortical development, I generated PTPRS conditional knockout mice in which I observed defects in radial neuron migration and cortical lamination. Enzymatic digestion of CPSGs in organotypic slice cultures show that CSPGs are also required for cortical neuron migration. Overall, this study identifies PTPRS as part of a regulatory mechanism involving NO and HDAC2, which is required for the radial migration of neurons and organisation of the cerebral cortex.
Supervisor: Riccio, A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available