Improving axon regeneration in the peripheral nervous system

The present proposal is on the phenomenon of excessive sprouting of regenerating nerve fibres that occurs after a lesion in the peripheral nervous system (PNS). In contrast to the central nervous system nerve fibers do regenerate in the PNS although in a clinically unsatisfactory manner. A major problem is excessive sprouting of regenerating axons, which results in aberrant reinnervation of target tissue and impaired functional recovery. Using an in vitro culture system of primary neurons and Schwann cells we discovered a novel signaling mechanism that modulates the branching of neurons in a highly specific manner. Sensory neurons cultured on Schwann cells which lack the reticulon protein Nogo-B displayed significantly less branching than their counterparts cultured on wildtype Schwann cells. We observed the same effect when blocking the Nogo-B receptor NgBR. Importantly, the long- distance growth of axons was not impeded in either experimental set -up. In the present research proposal we would like to investigate this finding in closer detail. 1) What is the signaling pathway downstream of NgBR that modulates branching of neurons? 2) Having obtained very robust and specific data in the cell culture system we consider it legitimate to test this novel mechanism in an in vivo nerve lesion model of the mouse. It is basic research like this that may provide the basis for novel strategies that will, for the first time, address the problem of excessive sprouting of regenerating peripheral nerve fibres.