title: Axon contact-driven Schwann cell dedifferentiation.
abstract: Mature Schwann cells (SCs) retain dedifferentiation potential throughout adulthood. Still, how dedifferentiation occurs remains uncertain. Results from a variety of cell-based assays using in vitro cultured cAMP-differentiated and myelinating SCs revealed the existence of a novel dedifferentiating activity expressed on the surface of dorsal root ganglion (DRG) axons. This activity had the capacity to prevent SC differentiation and elicit dedifferentiation through direct SC-axon contact. Evidence is provided showing that a rapid loss of myelinating SC markers concomitant to proliferation occurred even in the presence of elevated cAMP, a signal that is required to drive and maintain a differentiated state. The dedifferentiating activity was a membrane-bound protein found exclusively in DRG neurons, as judged by its subcellular partitioning, sensitivity to proteolytic degradation and cell-type specificity, and remained active even after disruption of cellular organization. It differed from the membrane-anchored neuregulin-1 isoforms that are responsible for axon contact-induced SC proliferation and exerted its action independently of mitogenic signaling emanating from receptor tyrosine kinases and mitogen-activated protein kinases such as ERK and JNK. Interestingly, dedifferentiation occurred without concomitant changes in the expression of Krox-20, a transcriptional enhancer of myelination, and c-Jun, an inhibitor of myelination. In sum, our data indicated the existence of cell surface axon-derived signals that override pro-differentiating cues, drive dedifferentiation and allow SCs to proliferate in response to axonal mitogens. This axonal signal may negatively regulate myelination at the onset or reversal of the differentiated state. GLIA 2017;65:851-863.
authors.affiliation: Miami Project to Cure Paralysis and Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, 33136.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Soto
authors.affiliation: Miami Project to Cure Paralysis and Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, 33136.
authors.forename: Paula V
authors.identifier: 0000-0002-5274-9238
authors.initials: PV
authors.lastname: Monje
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D054337:Cell Dedifferentiation / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000166:cytology / Q000502:physiology*; D012584:Sciatic Nerve / Q000166:cytology / Q000502:physiology
chemical_list: D051767:Early Growth Response Protein 2; D020890:Neuregulin-1; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4
keywords: cAMP; cell signaling; cell-cell interactions; differentiation; dorsal root ganglion neurons; in vitro systems; myelination; proliferation