Dean, Charlotte Hannah; (2001) The transcription factors dHAND and eHAND and the growth factor HGF are involved in peripheral nervous system development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A degenerate PCR screen was carried out on newborn mouse sciatic nerve in an attempt to identify basic helix loop helix (bHLH) transcription factors expressed in Schwann cells. As a result of this screen we identified low levels of expression of the bHLH factors eHAND and dHAND in Schwann cells. Digoxygenin in situ hybridisation studies using probes for eHAND and dHAND failed to detect these transcription factors in sciatic nerve, however expression was detected in the satellite glial cells of the sympathetic ganglia both pre and postnatally. No DHAND or eHAND expression was detected in dorsal root ganglia either by PCR or by in situ hybridisation. Overexpression studies and examination of dHAND and eHAND mutant mice revealed functional roles for these two genes in the peripheral nervous system. The role of the growth factor, hepatocyte growth factor (HGF) in the peripheral nervous system was also investigated, hi vitro studies revealed that HGF synergised vvuh -neuregulin (NRG) to increase the rate of division of both rat and mouse Schwann cell precursors whereas no such synergy was observed with basic fibroblast growth factor (bFGF). Little effect on survival of Schwann cell precursors was observed with HGF alone or with HGF in the presence of a low dose of either -NRG or bFGF in vitro. To investigate HGF function in vivo we examined wild-type and mutant embryos in which the HGF receptor Met was replaced with a loss of function version of the receptor, impaired in signal transduction. The Met receptor mutant metD/D carries a mutation in both of the phosphotyrosine residues present in the carboxy terminal tail that act as multifunctional docking sites and activate an array of transduction pathways. This mutation is severe and results in a phenotype identical to that of met null mutants. The the rate of Schwann cell precursor division in metD/D mutant mice was examined and these experiments confirmed the in vitro data already obtained. During the course of this study, it was noted that ganglion glial cells and Schwann cell precursors sometimes exhibited differences in gene expression and behaviour. In an attempt to clarify these observations a comparative study was carried out between these glial cell populations to establish whether these cells were inherently different. Results indicate that these cells are likely to show extensive similarities in molecular markers but, due to the influence of their particular environment may express different genes. More interestingly, the timing of development of these two glial cell populations differs, since satellite glial cells mature at an earlier time point than Schwann cell precursors.

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