title: The BMP coreceptor RGMb promotes while the endogenous BMP antagonist noggin reduces neurite outgrowth and peripheral nerve regeneration by modulating BMP signaling.
abstract: Repulsive guidance molecule b (RGMb) is a bone morphogenetic protein (BMP) coreceptor and sensitizer of BMP signaling, highly expressed in adult dorsal root ganglion (DRG) sensory neurons. We used a murine RGMb knock-out to gain insight into the physiological role of RGMb in the DRG, and address whether RGMb-mediated modulation of BMP signaling influences sensory axon regeneration. No evidence for altered development of the PNS and CNS was detected in RGMb(-/-) mice. However, both cultured neonatal whole DRG explants and dissociated DRG neurons from RGMb(-/-) mice exhibited significantly fewer and shorter neurites than those from wild-type littermates, a phenomenon that could be fully rescued by BMP-2. Moreover, Noggin, an endogenous BMP signaling antagonist, inhibited neurite outgrowth in wild-type DRG explants from naive as well as nerve injury-preconditioned mice. Noggin is downregulated in the DRG after nerve injury, and its expression is highly correlated and inversely associated with the known regeneration-associated genes, which are induced in the DRG by peripheral axonal injury. We show that diminished BMP signaling in vivo, achieved either through RGMb deletion or BMP inhibition with Noggin, retarded early axonal regeneration after sciatic nerve crush injury. Our data suggest a positive modulatory contribution of RGMb and BMP signaling to neurite extension in vitro and early axonal regrowth after nerve injury in vivo and a negative effect of Noggin.
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Chi H E
authors.initials: CH
authors.lastname: Ma
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Brenner
authors.forename: Takao
authors.initials: T
authors.lastname: Omura
authors.forename: Omar A
authors.initials: OA
authors.lastname: Samad
authors.forename: Michael
authors.initials: M
authors.lastname: Costigan
authors.forename: Perrine
authors.initials: P
authors.lastname: Inquimbert
authors.forename: Vera
authors.initials: V
authors.lastname: Niederkofler
authors.forename: Rishard
authors.initials: R
authors.lastname: Salie
authors.forename: Chia Chi
authors.initials: CC
authors.lastname: Sun
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
authors.forename: Silvia
authors.initials: S
authors.lastname: Arber
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Samad
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal; D002478:Cells, Cultured; D058851:GPI-Linked Proteins; D005727:Ganglia, Spinal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D012584:Sciatic Nerve / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D000099176:Noggin Protein; C483497:Rgmb protein, mouse