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Functions of the proto-oncogene Ski in the regulation of TGFbeta signalling and the control of Schwann cell proliferation, differentiation and apoptosis

Final Activity Report Summary - SKI IN SCHWANN CELLS (Functions of the proto-oncogene Ski in the regulation of TGFbeta signalling and the control of Schwann cell proliferation, differentiation ...) 

Unlike the central nervous system (CNS), peripheral nerves can regenerate efficiently. This ability is largely attributed to Schwann cells, glia cells of the peripheral nervous system, which are able to de-differentiate, proliferate and re-differentiate after injury, to foster axonal re-growth and re-build myelin sheaths. Schwann cells also constitute a key lineage in nerve development, supporting the survival of neurons and axons as well as providing myelination for efficient saltatory nerve conduction. Thus, understanding the regulatory mechanisms that guide Schwann cell proliferation, apoptosis, differentiation, de-differentiation and re-differentiation after injury is of paramount importance for nerve biology in health and disease.

TGFbeta is a key factor involved, triggering Schwann cell proliferation or apoptosis, depending on the cell maturation stage. Interestingly, the same growth factor can induce growth arrest and differentiation of epithelial cells. The mechanisms underlying these cell type-specific effects of TGFbeta on the cell cycle are largely unknown.

In the present study, we show that the proto-oncogene Ski is an important regulator of these effects. Indeed, we have found that Ski regulates proliferation depending on its level of expression, which turns on or off its interaction and cytoplasmic re-localisation with the tumour suppressor Retinoblastoma protein, segregating the latter away from the nucleus, where it exerts its activity.

A detailed understanding of the mechanisms controlling Schwann cell proliferation and survival are also of wider significance to provide the basis to develop treatment for peripheral nerve tumours (Schwann cell hyperplasia), inherited peripheral neuropathies, and common peripheral neuropathies secondary to diabetes, cancer chemotherapeutic agents, toxins and autoimmune disorders. In addition, Schwann cells are under evaluation in transplantation paradigms to augment regeneration, when accident-caused large gaps in peripheral nerves have occurred, and as auxiliary cells in non-regenerating CNS lesion (e.g. spinal cord repair). Profound knowledge of the control of Schwann cell proliferation and differentiation is of key importance for the success of such applications in regenerative medicine.