Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush.
Recovery after a spinal cord injury often requires that axons restore synaptic connectivity with denervated targets several centimeters from the site of injury. Here we report that systemic artemin (ARTN) treatment promotes the regeneration of sensory axons to the brainstem after brachial dorsal root crush in adult rats. ARTN not only stimulates robust regeneration of large, myelinated sensory axons to the brainstem, but also promotes functional reinnervation of the appropriate target region, the cuneate nucleus. ARTN signals primarily through the RET tyrosine kinase, an interaction that requires the nonsignaling coreceptor GDNF family receptor (GFRα3). Previous studies reported limited GFRα3 expression on large sensory neurons, but our findings demonstrate that ARTN promotes robust regeneration of large, myelinated sensory afferents. Using a cell sorting technique, we demonstrate that GFRα3 expression is similar in myelinated and unmyelinated adult sensory neurons, suggesting that ARTN likely induces long-distance regeneration by binding GFRα3 and RET. Although ARTN is delivered for just 2 wk, regeneration to the brainstem requires more than 3 mo, suggesting that brief trophic support may initiate intrinsic growth programs that remain active until targets are reached. Given its ability to promote targeted functional regeneration to the brainstem, ARTN may represent a promising therapy for restoring sensory function after spinal cord injury.
Department of Integrated Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111; and.
Laura Elisabeth
LE
Wong
Department of Integrated Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111; and.
Molly E
ME
Gibson
Neurology Research and.
H Moore
HM
Arnold
Chemical and Molecular Therapeutics, Biogen Idec, Inc., Cambridge, MA 02142.
Blake
B
Pepinsky
Department of Integrated Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111; and eric.frank@tufts.edu.
Eric
E
Frank
D000818:Animals; D001369:Axons / Q000502:physiology*; D001933:Brain Stem / Q000378:metabolism*; D019070:Cell Lineage; D002469:Cell Separation; D005434:Flow Cytometry; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism; D009409:Nerve Crush; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009445:Neuroanatomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000473:pathology*; D013126:Spinal Nerve Roots / Q000378:metabolism*
C490887:Artn protein, rat; C494995:Gfra3 protein, rat; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009419:Nerve Tissue Proteins
GFRα3; artemin; cuneate nucleus; dorsal root crush; regeneration