Novel pathways in nerve myelin formation
Similar to electrical wires, peripheral nerves get myelinated by Schwann cells, an essential process for normal nervous system function, repair and regeneration. Various acquired and inherited neuropathies emerge from a dysfunction in the myelination process. The growth of the myelin sheath is controlled, with the size and organisation being important determinants of nerve conduction velocity and myelin maintenance. However, the basic molecular mechanisms that contribute to longitudinal extension of the myelin sheath have not been defined. The aim of the EU-funded HEALTHYMYELIN (Molecular mechanisms of myelination in peripheral nerves) project was to dissect the mechanism underlying the regulation of myelin extension. The work focused on the polarity protein Crumbs3 (Crb3), which is expressed on Schwann cells. Researchers overexpressed or downregulated Crb3 and observed the effect on the formation of myelin sheath and on gaps between successive sheaths known as nodes of Ranvier. Targeting of Crb3 uncovered the existence of the Hippo/YAP pathway that negatively regulates myelin sheath elongation. The team proposed that myelin segments on an axon form harmoniously in concert with the growing nerve because axonal stretch activates YAP in Schwann cells. Furthermore, manipulation of pathway components indicated that modulation of YAP, via Crb3, provides a unique tool to control the quantity and location of myelin deposition in peripheral nerves. In addition, a defect in the Hippo/YAP pathway was found to be implicated in muscular dystrophy and could be significantly corrected via Crb3. Collectively, this novel insight into myelin elongation will help understand how myelin is formed during postnatal development. It also has therapeutic implications and the Crb3/HPO/YAP pathway can be engaged to reverse the phenotype of these disorders.
Keywords
Myelin, peripheral neuropathies, peripheral nerves, Schwann cells, Crb3, Hippo/YAP
