title: The actin-severing protein cofilin is downstream of neuregulin signaling and is essential for Schwann cell myelination.
abstract: Myelination is a complex process requiring coordination of directional motility and an increase in glial cell size to generate a multilamellar myelin sheath. Regulation of actin dynamics during myelination is poorly understood. However, it is known that myelin thickness is related to the abundance of neuregulin-1 (NRG1) expressed on the axon surface. Here we identify cofilin1, an actin depolymerizing and severing protein, as a downstream target of NRG1 signaling in rat Schwann cells (SCs). In isolated SCs, NRG1 promotes dephosphorylation of cofilin1 and its upstream regulators, LIM kinase (LIMK) and Slingshot-1 phosphatase (SSH1), leading to cofilin1 activation and recruitment to the leading edge of the plasma membrane. These changes are associated with rapid membrane expansion yielding a 35-50% increase in SC size within 30 min. Cofilin1-deficient SCs increase phosphorylation of ErbB2, ERK, focal adhesion kinase, and paxillin in response to NRG1, but fail to increase in size possibly due to stabilization of unusually long focal adhesions. Cofilin1-deficient SCs cocultured with sensory neurons do not myelinate. Ultrastructural analysis reveals that they unsuccessfully segregate or engage axons and form only patchy basal lamina. After 48 h of coculturing with neurons, cofilin1-deficient SCs do not align or elongate on axons and often form adhesions with the underlying substrate. This study identifies cofilin1 and its upstream regulators, LIMK and SSH1, as end targets of a NRG1 signaling pathway and demonstrates that cofilin1 is necessary for dynamic changes in the cytoskeleton needed for axon engagement and myelination by SCs.
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, Florida 32827, USA.
authors.forename: Nicklaus
authors.initials: N
authors.lastname: Sparrow
authors.forename: Maria Elisa
authors.initials: ME
authors.lastname: Manetti
authors.forename: Marga
authors.initials: M
authors.lastname: Bott
authors.forename: Tiffany
authors.initials: T
authors.lastname: Fabianac
authors.forename: Alejandra
authors.initials: A
authors.lastname: Petrilli
authors.forename: Margaret Longest
authors.initials: ML
authors.lastname: Bates
authors.forename: Mary Bartlett
authors.initials: MB
authors.lastname: Bunge
authors.forename: Stephen
authors.initials: S
authors.lastname: Lambert
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernandez-Valle
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D015153:Blotting, Western; D016764:Cell Polarity / Q000235:genetics; D049109:Cell Proliferation; D048429:Cell Size; D018920:Coculture Techniques; D051338:Cofilin 1 / Q000235:genetics* / Q000502:physiology*; D004396:Coloring Agents; D005260:Female; D005455:Fluorescent Antibody Technique; D022001:Focal Adhesions / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology; D054461:Lim Kinases / Q000235:genetics / Q000502:physiology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D020890:Neuregulin-1 / Q000235:genetics* / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000502:physiology* / Q000648:ultrastructure; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*
chemical_list: D051338:Cofilin 1; D004396:Coloring Agents; D008840:Microfilament Proteins; D020890:Neuregulin-1; C490580:Nrg1 protein, rat; D034741:RNA, Small Interfering; D054461:Lim Kinases; C515894:Limk1 protein, rat; C529152:SSH1 protein, rat; D010744:Phosphoric Monoester Hydrolases