REGULATION OF MYELINATION

  • Poduslo, Joseph F (PI)

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date4/1/843/31/95

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Neuroscience(all)

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