Reinduced Wnt signaling limits regenerative potential of sensory axons in the spinal cord following conditioning lesion.
Conditioning lesion of the peripheral branch of dorsal column axons is a well-known paradigm enabling the central branch to regenerate after injury to the spinal cord. However, only a small number of regenerating axons enter grafted substrates, and they do not grow beyond the lesion. We found that conditioning lesion induces, in addition to growth-stimulating genes, related to receptor tyrosine kinase (Ryk), a potent repulsive receptor for Wnts. Wnts are expressed around the site of spinal cord injury, and we found that grafted bone marrow stromal cells secreting the Wnt inhibitors secreted frizzled-related protein 2 or Wnt inhibitory factor 1 enhanced regeneration of the central branch after peripheral conditioning lesion. Furthermore, we found that Wnt4-expressing grafts caused dramatic long-range retraction of the injured central branch of conditioned dorsal root ganglion neurons. Macrophages accumulate along the path of receding axons but not around Wnt4-expressing cells, suggesting that the retraction of dorsal column axons is not a secondary effect of increased macrophages attracted by Wnt4. Therefore, Wnt-Ryk signaling is an inhibitory force co-induced with growth-stimulating factors after conditioning lesion. Overcoming Wnt inhibition may further enhance therapies being designed on the basis of the conditioning-lesion paradigm.
Neurobiology Section, Biological Sciences Division, University of California at San Diego, La Jolla, CA 92093, USA.
Edmund R
ER
Hollis
Yimin
Y
Zou
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D016026:Bone Marrow Transplantation; D005727:Ganglia, Spinal / Q000166:cytology; D008856:Microscopy, Fluorescence; D009416:Nerve Regeneration / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D020426:Sciatic Neuropathy / Q000503:physiopathology*; D011984:Sensory Receptor Cells / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology*; D017154:Stromal Cells / Q000637:transplantation; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060528:Wnt4 Protein / Q000378:metabolism
D060528:Wnt4 Protein; C555583:Wnt4 protein, rat