NEW SIGNALING PATHWAYS REGULATING SCHWANN CELLS OF THE PERIPHERAL NERVOUS SYSTEM: IMPLICATIONS IN PERIPHERAL NEUROPATHIES.

The origin, development and maturation of Schwann cells (SCs), the main glial cells of the peripheral nervous system (PNS), are a set of complicated and intriguing processes. These multifactorial processes take place following a precise and unique coordination between different molecules and intracellular signaling, that interact with a complex of endogenous and exogenous signals. Among these, there are integrins, neuregulins, growth factors, hormones, neurotransmitters and intracellular pathway, including protein kinase A and protein kinase C (PKA and PKC), serine/threonine kinase 1 (AKT), extracellular regulated MAPK/mitogen-activated protein kinase 1 (ERK/MAPK), Hippo, mechanistic target of rapamycin (mTOR), etc. This thesis is focused on some novel intracellular signaling pathways involved in the SCs development and maturation, from their origin to the acquisition of the myelinating or repairing phenotype. The first part of the thesis focuses on a proto-oncogene, the non-receptor tyrosine kinase SRC (SRC), and the focal adhesion kinase (FAK), which are intermediate pathways known to play a role in the control of adhesion, motility, and migration of SCs. It has been investigated whether these pathways are regulated by allopregnanolone (ALLO), a neuroactive steroid of peculiar interest for the control of SCs maturation. The second part of this thesis focuses on the study of the Hippo signaling pathway, known to be a key regulator of proliferation, apoptosis, control of organ size and crucial for cancer proliferation. Hippo pathway has been studied in SCs, where it is linked to Merlin (an oncosuppressor protein) and Yes associated protein/tafazzin (YAP/TAZ) factors. Interestingly, these mechanisms were responsive to physical and environmental challenges. Lastly, the third part of this thesis move on studying the role of the g-aminobutyric acid (GABA) system in the control of peripheral myelination. In particular, the whole expression profile was investigated in conditional knock out mice for the B1 subunit of the GABA-B receptor (GABA-B R), with a specific deletion in SCs. By the use of microarray technology, several genes resulted up- or downregulated in SCs, opening new perspectives on the possible targets downstream GABA-B R in SCs. Overall, these results highlight new aspects of the SCs biology, shedding light on unraveled mechanisms and underlying their importance in the development and maturation of these specialized cells of the PNS. This may be of pharmacological and therapeutically interest, in order to identify reliable approaches for the treatment of PNS diseases.