Hoving, JJA; (2016) Homotypic and heterotypic interactions in the peripheral nervous system. Doctoral thesis , UCL (University College London).

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	Spreadsheet Hoving_Table 1 EtOH-IgG UniProtSwall-Rattus.xlsx Download (800kB)
	Spreadsheet Hoving_Table 2 EtOH-N-Cadherin UniProtSwall-Rattus.xlsx Download (831kB)
	Spreadsheet Hoving_Table 3 TMX-IgG UniProtSwall-Rattus.xlsx Download (641kB)
	Spreadsheet Hoving_Table 4 TMX-N-cadherin UniProtSwall-Rattus.xlsx Download (887kB)

Abstract

Peripheral nerves have a remarkable ability to regenerate following a transection injury. To achieve this, Schwann cells collectively migrate as cords, taking regrowing axons across newly formed tissue known as the bridge that forms to reconnect the two nerve stumps. The Schwann cell cords themselves are guided by a newly formed polarised vasculature that provides a conducive environment for Schwann cell migration. Here we show, that in addition to mediating Schwann cell clustering, N-cadherin is required for contact inhibition of locomotion (CIL) in Schwann cells, which may be required to produce an outward force within the cords of collectively migrating Schwann cells. Mechanistically we show that N-cadherin regulates CIL independent of its traditional mechanism of trans-homodimerisation and independent of adherence junction components. Instead, the extracellular domain of N-cadherin is sufficient to mediate CIL, which appears to present a repulsion (co-)signal to the other cell. We further show, that CIL is disrupted in Schwann cells expressing oncogenic Ras in a MEK-dependent manner, not through loss of N-cad, but through loss of a distinct signal. Ras-Raf-MEK-ERK signalling alters the mRNA expression levels of ephrins and Eph receptors, and we show using Co-IP and mass spectrometry, that oncogenic Ras changes the interaction profile of N-cadherin proteins and show a potential role for glypican-4 and ephrin-A1 in CIL. Finally, we show that migration of Schwann cells along the vasculature is independent of focal adhesion complexes, consistent with the more amoeboid-mode of migration observed along the blood vessels.

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