Novel players on the stage of myelination

October 31st 2014
Versione stampabile

Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (TN) - Room B104
 at 2:00 p.m.

  • Carla Taveggia, Group Leader of Axo-Glia Interaction Unit San Raffaele Scientific Institute, Milan, Italy

Myelin derives from the spiral wrapping of glial cells and is essential for efficient and rapid propagation of action potentials along neurites. Communication between glial cells and neurons is crucial for nerve development, yet their reciprocal interactions have remained elusive. Glial cells promote neuronal survival, regulate the organization of myelinated axons and promote axonal differentiation and myelin sheath production. In turn, neurons promote proliferation, survival of glial cells and formation of myelin. We previously showed that axonal Neuregulin1 (NRG1) type III is an essential instructive signal for myelination in the peripheral nervous system (PNS). Above a threshold level of expression, axons are myelinated and the amount of myelin and its thickness, are graded to its axonal levels. All NRG1 proteins are activated by proteases-mediated extracellular cleavage. NRG1 type III is cleaved in the extracellular region by the α-secretase TACE and the β-secretase BACE1. While BACE1 cleavage of NRG1 type III promotes myelination, we recently reported that TACE cleaves NRG1 and inhibits myelination by competing with BACE1, thus identifying a novel mechanism regulating PNS myelination. NRG1 type III is also processed in the intracellular domain by the γ-secretase complex. We now show that NRG1 type III intracellular cleavage and nuclear translocation specifically upregulates the expression of prostaglandins. These studies identify a novel pharmacologically accessible pathway whose activity could be modulated to promote myelin formation and maintenance. The overall goal of our studies is to provide novel insights into the axonal regulation of myelination. Since it is likely that both myelination and remyelination acts through common mechanisms, the identification of the axonal molecules involved in myelination could be translated in research aimed at applications in demyelinating disorders, in which disability is correlated to myelin and axonal loss.