The regulatory mechanisms that control myelin gene expression in the peripheral nervous system are largely unknown. Further understanding of the transcriptional, translational, and posttranslational regulation of myelin gene expression will provide important information for advancing our understanding of human disease where demyelination is prominent as in, for example, the demyelinating peripheral neuropathies. The paradigms of crush injury and permanent transection of the adult rat sciatic nerve (classical Wallerian degeneration) have proven to be excellent models for evaluating the regulation of myelin gene expression. These experimental animal models of neuropathy are characterized by the presence and absence of axonal regeneration and subsequent myelin assembly. Past efforts supported by this grant have focused on PO, the major glycoprotein of peripheral nerve myelin, where transcriptional, translational, and posttranslational regulation of PO expression has been demonstrated. I now propose a conceptionally new direction of research which addresses the mechanism of myelin gene induction and the role that the axon plays in this induction in the normal, crushed, and permanently transected nerve. Pilot data are presented which demonstrate the forskolin treatment of endoneurial segments of rat sciatic nerve results in increased cAMP and PO mRNA levels in normal and crushed nerves, but not in the permanently transected nerves. These results provide a working hypothesis that the presence of the axon is required for the observed increase of cAMP and PO mRNA levels and suggest that the cAMP increase occurs within the axon which then activates a different Schwann cell second messenger pathway to induce PO gene expression. Experiments are proposed to test this hypothesis. In addition to the further characterization of PO regulation, I now plan to extend this analysis to evaluate the regulation of other myelin genes and their products, including MBP, P2, MAG, and CNPase (as well as gangliosides) in these two models as a function of time after both injuries compared to the normal adult nerve and the nerve during development. Such experiments will address whether other myelin related genes and their products are regulated in similar or different ways. Because of the observation supported by this grant that PO is posttranslationally degraded in lysosomes after permanent transection injury, the pathways and mechanisms by which other myelin proteins are catabolized after nerve transection will be evaluated. Understanding these different catabolic pathways will aid in deciphering the mechanisms of demyelination as observed in various demyelinating human neuropathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020551-10
Application #
2263895
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1984-04-01
Project End
1995-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Poduslo, J F; Walikonis, R S; Domec, M C et al. (1995) The second messenger, cyclic AMP, is not sufficient for myelin gene induction in the peripheral nervous system. J Neurochem 65:149-59
LeBlanc, A C; Pringle, J; Lemieux, J et al. (1992) Regulation of 2',3'-cyclic nucleotide phosphodiesterase gene expression in experimental peripheral neuropathies. Brain Res Mol Brain Res 15:40-6
LeBlanc, A C; Windebank, A J; Poduslo, J F (1992) P0 gene expression in Schwann cells is modulated by an increase of cAMP which is dependent on the presence of axons. Brain Res Mol Brain Res 12:31-8
Brunden, K R; Windebank, A J; Poduslo, J F (1990) Role of axons in the regulation of P0 biosynthesis by Schwann cells. J Neurosci Res 26:135-43
Gupta, S K; Poduslo, J F; Dunn, R et al. (1990) Myelin-associated glycoprotein gene expression in the presence and absence of Schwann cell-axonal contact. Dev Neurosci 12:22-33
Brunden, K R; Poduslo, J F (1990) Posttranslational degradation of the major myelin glycoprotein by Schwann cells in vivo and in vitro. Ann N Y Acad Sci 605:230-9
Kohriyama, T; Yu, R K; Berg, C T et al. (1990) Sulfate incorporation into peripheral nerve endoneurial glycolipids after crush and permanent transection injury. J Neurosci Res 26:144-8
LeBlanc, A C; Poduslo, J F (1990) Regulation of apolipoprotein E gene expression after injury of the rat sciatic nerve. J Neurosci Res 25:162-71
LeBlanc, A C; Poduslo, J F (1990) Axonal modulation of myelin gene expression in the peripheral nerve. J Neurosci Res 26:317-26
Brunden, K R; Windebank, A J; Poduslo, J F (1990) Catabolic regulation of the expression of the major myelin glycoprotein by Schwann cells in culture. J Neurochem 54:459-66

Showing the most recent 10 out of 23 publications