Resumen de New insights into mechanisms controlling the schwann cell phenotype during tumourigenesis and after injury
Schwann cells are highly plastic, having the ability to revert their phenotype through most of the different stages in their development. They can therefore shift from a myelinating phenotype back to a dedifferentiated and proliferative phenotype. This property is essential for Schwann cell acquisition of a repair phenotype after a nerve injury, which enables nerve regeneration in the mouse. However, this plasticity can facilitate an uncontrolled hyperproliferation of Schwann cells under tumourigenic conditions. The overexpression of NRG1 type III-ß3 in NSE-SMDF(+/-) mice causes Schwann cell overproliferation during the first postnatal days, which leads to the formation of neurofibroma-like nerves in these mice. However, this overproliferation is halted after P14 even though the mitogenic signal still remains. In the first part of this thesis, we demonstrate that this halt in Schwann cell overproliferation is due to the activation of the Oncogenic Induced Senescence (OIS) program, as two key mediators of this program, p16Ink4a and p19Arf, are upregulated in the nerves of NSE-SMDF(+/-) mice. We also show that the OIS program is activated in neurofibromas of NF1 patients. Additionally we demonstrate that the blockage of the p19Arf/p53 pathway in the nerves of NSE-SMDF(+/-) mice causes Schwann cells to resume proliferation, leading to the formation of malignant tumours in the PNS. As well as in neurofibromas, the activation of OIS mediates Schwann cell proliferation arrest during Wallerian degeneration after a nerve injury, in order to prevent the putative formation of a tumour.
Induction and maintenance of the myelinating phenotype in Schwann cells is mediated through axonal signals that elevate the intracellular cAMP levels in Schwann cells. In cultured Schwann cells, elevation of cAMP mimics axonal contact and leads to the upregulation of myelin proteins and the downregulation of c-Jun, a transcription factor that characterizes dedifferentiation and is crucial for the repair phenotype of denervated Schwann cells in Wallerian degeneration. In the second part of this thesis, we demonstrate that the repression of c-Jun expression by cAMP is mediated through the translocation of HDAC4 to the nucleus, where it probably interacts with the promoter of c-Jun and recruits HDAC3 to repress the transcription. We also show preliminary data that suggests the involvement of Schwann cell adrenergic receptors in mediating the axonal signals that induce Schwann cell differentiation.
