A number of genes have been discovered that are responsible for the demyelinating diseases of the peripheral nervous system. Exploring the mechanisms of demyelination caused by alterations in these genes also illuminates the molecular mechanisms of myelination. For example, it appears that mutations in the peripheral myelin protein 22 (PMP22) gene differentially alter the interactions of the PMP22 protein and in turn alter its trafficking pattern. An offshoot of these studies was the discovery that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3), besides being survival factors for sensory neurons, are also mediators of the myelination process. In this proposed study the identity and location of the neurotrophin receptors that are responsible for the actions of BDNF and NT3 will be determined. The experiments involve the use of function blocking antibodies or receptor antibodies and of neurotrophin mutants that bind selectively to either the trk receptors or to the p75NTR. Location of the receptors will probed by in situ hybridization. Two complementary myelination systems will be used, one in cocultures of sensory neurons and Schwann cells and the other in the developing sciatic nerve. The expression of the receptors identified in cocultures will be explored in the in vivo system and in the developing sciatic nerve of viable animals deficient in appropriate neurotrophin receptors or neurotrophins. Besides identifying one more ligand-receptor system involved in myelination the data may also aid in considering the therapeutic application of neurotrophins in the peripheral demyelinating disease.
