Varela Mendes Ribeiro, A.S.; (2012) A novel model of tumour formation in NF1. Doctoral thesis , UCL (University College London).

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Abstract

Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes to the development of heterogeneous tumours of Schwann cell origin, termed neurofibromas. Neurofibromas are thought to arise from a combination of genetic events – loss of the Ras-GAP neurofibromin in the Schwann cell lineage – and microenvironmental cues. Schwann cells are specialised cells that ensheath and myelinate the axons in the peripheral nervous system (PNS). In the adult they are present in a quiescent state, however following damage to the PNS they have a remarkable ability to regenerate. Distal to the site of injury, Schwann cells dedifferentiate to a progenitor-like state, in which they contribute to nerve repair by recruiting a robust inflammatory response and helping axons return to their targets. Work from our laboratory has shown that activation of the Ras/Raf/ERK pathway plays a central role in driving the switch in Schwann cell state from a fully differentiated to a proliferating, “progenitor-like” cell. Crucially, neurofibromas resemble injured nerves in that they are composed of a mixture of inflammatory cells and Schwann cells that are found dedifferentiated and dissociated from axons, suggesting that deregulation of Ras/ERK may trigger tumourigenic events. In this thesis I present work on how the Ras/Raf/ERK pathway may be regulated in Schwann cells. I show that the phosphatase MKP3 may be involved in controlling the levels of ERK activity in Schwann cells during differentiation and following nerve injury. I also describe a new model for neurofibroma formation. Using transgenic mice I show that Nf1 loss in adult, myelinating Schwann cells has no effect on peripheral nerves and does not induce tumourigenesis. However, when coupled with an injury, the mice developed tumours at a high frequency. Furthermore, I show that in the absence of Nf1, ERK signalling is deregulated upon injury, implicating this pathway in the tumour formation. This may have therapeutic relevance, which is currently being tested in our animal model. In addition, we observed that tumours only arise at the wound site, despite Schwann cells dedifferentiating along the length of the nerve. This strongly implies that the microenvironment is a crucial player in the outcome of Nf1 loss and reveals this new animal model as a promising system to further dissect molecular events involved in tumourigenesis.

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