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The Journal of Neuroscience, July 15, 2001, 21(14):5130-5138
The Leukocyte Common Antigen-Related Protein Tyrosine Phosphatase
Receptor Regulates Regenerative Neurite Outgrowth In
Vivo
Youmei
Xie,
Tracy T.
Yeo,
Cheng
Zhang,
Tao
Yang,
Michelle A.
Tisi,
Stephen M.
Massa, and
Frank M.
Longo
Department of Neurology, University of California, San
Francisco/Veteran's Administration Medical Center, San Francisco,
California 94121
Drosophila and leech models of nervous system
development demonstrate that protein tyrosine phosphatase (PTP)
receptors regulate developmental neurite outgrowth. Whether PTP
receptors regulate neurite outgrowth in adult systems or in
regenerative states remains unknown. The leukocyte common
antigen-related (LAR) receptor is known to be present in rodent
dorsal root ganglion (DRG) neurons; therefore, the well established
model of postcrush sciatic nerve regeneration was used to test the
hypothesis that LAR is required for neurite outgrowth in the adult
mammalian nervous system. In uninjured sciatic nerves, no differences
in nerve morphology and sensory function were detected between
wild-type and LAR-deficient littermate transgenic mice. Sciatic nerve
crush resulted in increased LAR protein expression in DRG neurons. In
addition, nerve injury led to an increase in the proportion of LAR
protein isoforms known to have increased binding affinity to
neurite-promoting laminin-nidogen complexes. Two weeks after nerve
crush, morphological analysis of distal nerve segments in LAR-deficient
transgenic mice demonstrated significantly decreased densities of
myelinated fibers, decreased axonal areas, and increased myelin/axon
area ratios compared with littermate controls. Electron microscopy
analysis revealed a significant twofold reduction in the density of
regenerating unmyelinated fibers in LAR / nerves distal to the crush
site. Sensory testing at the 2 week time point revealed a corresponding
3 mm lag in the proximal-to-distal progression of functioning sensory
fibers along the distal nerve segment. These studies introduce PTP
receptors as a major new gene family regulating regenerative neurite
outgrowth in vivo in the adult mammalian system.
Key words:
LAR; protein tyrosine phosphatase receptor; PTP; nerve
regeneration; sciatic nerve; dorsal root ganglion; neurite
outgrowth
Copyright © 2001 Society for Neuroscience 0270-6474/01/21145130-09$05.00/0
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