Pleiotrophin is a neurotrophic factor for spinal motor neurons

doi:10.1073/pnas.0603243104

Pleiotrophin is a neurotrophic factor for spinal motor neurons

Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287

Edited by Thomas M. Jessell, Columbia University Medical Center, New York, NY, and approved January 18, 2007 (received for review April 21, 2006)

Abstract

Regeneration in the peripheral nervous system is poor after chronic denervation. Denervated Schwann cells act as a “transient target” by secreting growth factors to promote regeneration of axons but lose this ability with chronic denervation. We discovered that the mRNA for pleiotrophin (PTN) was highly up-regulated in acutely denervated distal sciatic nerves, but high levels of PTN mRNA were not maintained in chronically denervated nerves. PTN protected spinal motor neurons against chronic excitotoxic injury and caused increased outgrowth of motor axons out of the spinal cord explants and formation of “miniventral rootlets.” In neonatal mice, PTN protected the facial motor neurons against cell death induced by deprivation from target-derived growth factors. Similarly, PTN significantly enhanced regeneration of myelinated axons across a graft in the transected sciatic nerve of adult rats. Our findings suggest a neurotrophic role for PTN that may lead to previously unrecognized treatment options for motor neuron disease and motor axonal regeneration.

Footnotes

*To whom correspondence should be addressed at:
Department of Neurology, Johns Hopkins University, 600 North Wolfe Street, Path 509, Baltimore, MD 21287.
E-mail: ahoke{at}jhmi.edu
Author contributions: R.M., W.C., and A.H. designed research; R.M., W.C., and A.H. performed research; R.M., W.C., and A.H. analyzed data; and R.M. and A.H. wrote the paper.
This article is a PNAS direct submission.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0603243104/DC1.
Abbreviations:

ALK,

anaplastic lymphoma kinase;

DRG,

dorsal root ganglion;

GDNF,

glial cell line-derived neurotrophic factor;

GFAP,

glial fibrillary acidic protein;

PTN,

pleiotrophin;

THA,

threohydroxyaspartate.