title: Intrinsic facilitation of adult peripheral nerve regeneration by the Sonic hedgehog morphogen.
abstract: Intrinsic molecular determinants of neurodevelopmental outcomes assume new, albeit related roles during adult neural regeneration. Here we studied and identified a facilitatory role for Sonic hedgehog protein (Shh), a morphogen that influences motor neuron floor plate architecture, during adult peripheral neuron regeneration. Shh and its receptors were expressed in adult dorsal root ganglia (DRG) neurons, axons and glia and trended toward higher levels following axotomy injury. Knockdown of Shh in adult sensory neurons resulted in decreased outgrowth and branching in vitro, identifying a role for Shh in facilitating outgrowth. The findings argued for an intrinsic action to support neuron regeneration. Support of advancement and turning however, were not identified in adult sensory neuron growth cones in response to local extrinsic gradients of Shh. That intrinsic Shh supported the regrowth of peripheral nerves after injury was confirmed by the analysis of axon regrowth from the proximal stumps of transected sciatic nerves. By exposing regenerating axons to local infusions of Shh siRNA in vivo within a conduit bridging the transected proximal and distal stumps, we achieved local knockdown of Shh. In response, there was attenuated axonal and Schwann cell outgrowth beyond the transection zone. Unlike its role during neurodevelopment, Shh facilitates but does not confer regenerative outgrowth properties to adult neurons alone. Exploring the differing properties of morphogens and related proteins in the adult nervous system identifies new and important roles for them.
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez
authors.affiliation: Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Anand
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Division of Anatomy, Department of Surgery, University of Alberta, Edmonton, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Webber
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Christie
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: GuiFang
authors.initials: G
authors.lastname: Guo
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Vandana
authors.initials: V
authors.lastname: Singh
authors.affiliation: Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address: zochodne@ualberta.ca.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Zochodne
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000502:physiology; D000072079:Patched Receptors; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000473:pathology / Q000503:physiopathology*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface
keywords: Nerve injury; Peripheral nerve; Regeneration; Sonic hedgehog protein