The vertebrate nervous system develops and functions through a set of cellular interactions. Among the most striking of these interactions is one that occurs between neurons and glia, and results in the elaboration of the myelin sheath, the electrical insulation that surrounds all rapidly conducting axons. For the glial cells that elaborate myelin, production of the sheath involves a drastic reorganization of both morphology and metabolism, including the induction and high-level expression of a set of genes and proteins unique to myelin-forming cells. This proposal is concerned with the identification and functional characterization of the genes that mediate glial cell differentiation and myelination. Specific questions addressed include: By what mechanisms are myelination-specific genes induced and regulated? What role do neurons play in these processes? What are the cis-acting regulatory elements of these genes that control their cell-specific transcription and what are the trans-acting proteins that bind these elements? When and where are myelination genes expressed during neural development? And what can we learn of the function of the proteins these genes encode? To address these and related questions requires both probes for the relevant genes and proteins, as well as the ability to manipulate the cellular environment and development of myelinating glia. The experiments described below therefore employ the techniques of eukaryotic molecular genetics and the in vitro culture of purified glial cells and cell lines, in conjunction with the application of recombinant DNA and antibody probes for glial- specific genes and proteins. The ultimate goal of this work is the delineation of the molecular pathway of myelin formation during normal development. Additionally, it may provide an understanding of glial gene expression and protein metabolism under circumstances in which glia are deprived of the influence of neurons, as occurs in central and peripheral neuropathies, and during episodes of demyelination and remyelination, as occur in Multiple Sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023896-12
Application #
2416278
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1986-07-01
Project End
2001-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
12
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Krappa, R; Nguyen, A; Burrola, P et al. (1999) Evectins: vesicular proteins that carry a pleckstrin homology domain and localize to post-Golgi membranes. Proc Natl Acad Sci U S A 96:4633-8
Brown, A M; Lemke, G (1997) Multiple regulatory elements control transcription of the peripheral myelin protein zero gene. J Biol Chem 272:28939-47
Monuki, E S; Kuhn, R; Weinmaster, G et al. (1990) Expression and activity of the POU transcription factor SCIP. Science 249:1300-3
Trapp, B D; Hauer, P; Lemke, G (1988) Axonal regulation of myelin protein mRNA levels in actively myelinating Schwann cells. J Neurosci 8:3515-21