title: Nerve injury induces glial cell line-derived neurotrophic factor (GDNF) expression in Schwann cells through purinergic signaling and the PKC-PKD pathway.
abstract: Upon peripheral nerve injury, specific molecular events, including increases in the expression of selected neurotrophic factors, are initiated to prepare the tissue for regeneration. However, the mechanisms underlying these events and the nature of the cells involved are poorly understood. We used the injury-induced upregulation of glial cell-derived neurotrophic factor (GDNF) expression as a tool to gain insights into these processes. We found that both myelinating and nonmyelinating Schwann cells are responsible for the dramatic increase in GDNF expression after injury. We also demonstrate that the GDNF upregulation is mediated by a signaling cascade involving activation of Schwann cell purinergic receptors, followed by protein kinase C signaling which activates protein kinase D (PKD), which leads to increased GDNF transcription. Given the potent effects of GDNF on survival and repair of injured peripheral neurons, we propose that targeting these pathways may yield therapeutic tools to treat peripheral nerve injury and neuropathies.
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, MA, USA.
authors.forename: Pin
authors.initials: P
authors.lastname: Xu
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Rosen
authors.forename: Kristian
authors.initials: K
authors.lastname: Hedstrom
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Rey
authors.forename: Sushovan
authors.initials: S
authors.lastname: Guha
authors.forename: Courtney
authors.initials: C
authors.lastname: Hart
authors.forename: Gabriel
authors.initials: G
authors.lastname: Corfas
mesh_terms: D000818:Animals; D019771:Axotomy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D008297:Male; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011983:Receptors, Purinergic / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000473:pathology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D011983:Receptors, Purinergic; D012694:Serine; C089212:protein kinase D; D011493:Protein Kinase C
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