In spite of the medical importance of myelin, as evidenced by the debilitating effects of demyelinating diseases, little is known about the genetic regulatory mechanisms that control myelin synthesis. Axonal contact triggers myelination through as yet unknown signal(s), many of which can be mimicked in Schwann cells by treatment with the adenylyl cyclase activator forskolin. The POU domain transcription factor Oct-6 (also known as Tst-1 or SCIP) is one of the genes that is induced by forskolin. The phenotypes of mice that lack Oct-6 reveal that it plays a critical role in controlling the timing and rate of peripheral myelination, but the mechanisms by which it does so are unknown. A screen for additional forskolin-regulated genes produced clones for the ERK2-specific phosphatases MKP-3, and the sphingosine-1 phosphate (S1P) receptor edg-3. To better understand the role of these signal transduction molecules in Schwann cell differentiation, the first Specific Aim of this application will study their expression patterns in Schwann cells, and their ability to activate differentiation markers such as Oct-6 in sciatic nerve, of which the functions and/or identifies of five are unknown. The second Specific Aim of this application is to characterize these Oct-6 induced genes genes further. The two known genes that are activated by Oct-6, the cytoplasmic LIM domain protein CRP2, and the fatty acid transport protein myelin P2, suggest cytoskeletal rearrangement or fatty acid transport as rate-limiting steps in myelination. Both genes possess putative Oct-6 binding sites in their promoters. The hypothesis that Oct-6 directly regulates the expression of these genes will be tested in the third Specific Aim of this application. In the fourth Specific Aim, it is proposed to study postnatal functions of Oct-6 in peripheral myelination using mice that lack the gene only in Schwann cells.
