title: Schwann cells direct peripheral nerve regeneration through the Netrin-1 receptors, DCC and Unc5H2.
abstract: In the peripheral nervous system, Schwann cells (SCs) promote nerve regeneration by the secretion of trophic support molecules and the establishment of a supportive growth matrix. Elucidating factors that promote SC outgrowth following nerve injury is an important strategy for improving nerve regeneration. We identified the Netrin-1 receptors, Deleted in Colorectal Cancer (DCC) and Uncoordinated (Unc)5H2 as SC receptors that influence nerve regeneration by respectively promoting or inhibiting SC outgrowth. Significantly, we show both DCC and Unc5H2 receptors are distributed within SCs. In adult nerves, DCC is localized to the paranodes and Schmidt-Lantermann incisures of myelinating SCs, as well as along unmyelinated axons. After axotomy, DCC is prominently expressed in activated SCs at the regenerating nerve front. In contrast, Unc5H2 receptor is robustly distributed in myelinating SCs of the intact nerve and it is found at low levels in the SCs of the injury site. Local in vivo DCC siRNA mRNA knockdown at the growing tip of an injured nerve impaired SC activation and, in turn, significantly decreased axon regeneration. This forced DCC inhibition was associated with a dramatic reciprocal upregulation of Unc5H2 in the remaining SCs. Local Unc5H2 knockdown at the injury site, however, facilitated axon regrowth, indicating it has a role as an intrinsic brake to peripheral nerve regeneration. Our findings demonstrate that in adult peripheral nerves, SCs respond to DCC and Unc5H2 signaling, thereby promoting or hindering axon outgrowth and providing a novel mechanism for SC regulation during nerve regeneration.
authors.affiliation: Division of Anatomy, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. webber2@ualberta.ca
authors.forename: Christine A
authors.initials: CA
authors.lastname: Webber
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Christie
authors.forename: Chu
authors.initials: C
authors.lastname: Cheng
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez
authors.forename: Bhagat
authors.initials: B
authors.lastname: Singh
authors.forename: Vandana
authors.initials: V
authors.lastname: Singh
authors.forename: Dorothy
authors.initials: D
authors.lastname: Thomas
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Zochodne
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D000075389:DCC Receptor; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D009416:Nerve Regeneration / Q000502:physiology*; D000075386:Netrin Receptors; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000075389:DCC Receptor; C501912:Dcc protein, rat; D005904:Glial Fibrillary Acidic Protein; D000075386:Netrin Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C524887:Unc5b protein, rat