title: Disruption of fibroblast growth factor receptor signaling in nonmyelinating Schwann cells causes sensory axonal neuropathy and impairment of thermal pain sensitivity.
abstract: Axon-glial interactions are critical for normal functioning of peripheral nerves, and their disruption leads to peripheral neuropathies. Fibroblast growth factors (FGFs) are key players in peripheral nerve regeneration after injury. We investigated the role of FGF receptor (Fgfr) signaling in Schwann cells and the consequent regulation of normal Schwann cell-axon interactions. Fgfr1 and Fgfr2 were conditionally inactivated, either singly or in combination, in myelinating and nonmyelinating Schwann cells (NMSCs) of transgenic mice. The double mutant mice displayed significant loss of thermal sensitivity accompanied by marked neuropathy of unmyelinated nociceptive sensory axons terminating in the dorsal horn of spinal cords, the primary site for integrating pain and temperature inputs. Neuropathy, although to a lesser extent, was also observed in the nociceptive C-fibers in the Remak bundles of sciatic nerves; however, there was no loss of NMSCs that ensheathe these axons. Furthermore, axons wrapped by myelinating Schwann cells and associated myelin sheaths appeared to be unaffected. Relative to the double mutants, axonal neuropathy developed much later in the Fgfr1 but not Fgfr2 single mutant, indicating a difference in signaling potential of the two receptors, with Fgfr1 being more robust than Fgfr2. These findings emphasize the importance of Fgfr1 and Fgfr2 signaling as potential mediators of axon-glial interaction in the peripheral sensory pain pathway primarily via influencing NMSC function, which in turn modulates the structure and function of unmyelinated sensory axons. This study provides a novel molecular mechanism for nociception with possible implications for pain sensitivity in peripheral sensory neuropathies.
authors.affiliation: Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030-3401, USA.
authors.forename: Miki
authors.initials: M
authors.lastname: Furusho
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Dupree
authors.forename: Melissa
authors.initials: M
authors.lastname: Bryant
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bansal
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology*; D006358:Hot Temperature / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D017468:Receptors, Fibroblast Growth Factor / Q000172:deficiency* / Q000235:genetics; D012583:Schwann Cells / Q000473:pathology / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000473:pathology* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D017468:Receptors, Fibroblast Growth Factor