NR/CAM AND FORMATION OF NODE OF RANVIER

Project Details

Description

DESCRIPTION (Verbatim from the Applicant's Abstract): Myelinated nerve fibers
are critical for efficient propagation of impulses via saltatory conduction.
Myelin is organized anatomically and physiologically into longitudinal segments
(internodes) that are interrupted by the nodes of Ranvier. High concentrations
of voltage-gated sodium channels are located in the node, and specific
potassium channels are restricted primarily to the paranodal regions. The nodes
are critical for saltatory conduction along the nerve, but the molecular
signals that determine node formation are poorly understood. Recent studies
demonstrated that a subset of cell adhesion molecules (CAMs) in the Ig
Superfamily (i.e., Nr-CAM and neurofascin) are specifically localized to the
node at early stages of its formation.

We have recently demonstrated that a recombinant form of Nr-CAM can perturb
node formation using a co-culture system involving dorsal root ganglion (DRG)
neurons and Schwann cells. The results strongly indicate a role for Nr-CAM and
its ligands in node formation. Therefore, we propose to explore the functions
of Nr-CAM and proteins that can interact with it, i.e., TAG-1, contactin,
RPTPbeta, neurofascin and ankyrin, in the formation and maintenance of the node
of Ranvier.

Our first goal is to determine the patterns of expression of Nr-CAM and
proteins known to interact with it in neurons and Schwann cells at different
stages of nerve differentiation. We will also use mice that we have recently
generated that are null for the Nr-CAM protein to search for potential
alterations in the structure and development of the node and in nerve
conduction. Our second goal is to analyze the role of Nr-CAM and proteins that
can interact with it in node formation using a Schwann cell-neuron co-culture
system. Recombinant forms of CAMs as Fc fusion proteins and specific antibodies
against Nr-CAM and its binding partners will be used to test their ability to
perturb node formation in the co-culture system. Node formation will be
analyzed by staining with antibodies against ankyrin and sodium channels that
normally become clustered at the nodes in culture. Our third goal is to
identify specific binding regions in the Nr-CAM receptors involved in node
formation and to analyze molecular mechanisms that signal protein clustering at
nodes.

The proposed studies will clarify the functions of Nr-CAM and its binding
partners in node development in the PNS and may also provide new insights into
the molecular basis of nerve development in the CNS. In the future, such
information may lead to new therapeutic strategies to prevent injury and
restore function in myelinated nerves that become damaged and remyelinated in
multiple sclerosis.
StatusFinished
Effective start/end date7/3/996/30/04

Funding

  • National Institute of Neurological Disorders and Stroke: $234,643.00
  • National Institute of Neurological Disorders and Stroke: $227,818.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $241,301.00

ASJC

  • Cell Biology

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