title: Profilin 1 is required for peripheral nervous system myelination.
abstract: Myelination allows rapid saltatory propagation of action potentials along the axon and is an essential prerequisite for the normal functioning of the nervous system. During peripheral nervous system (PNS) development, myelin-forming Schwann cells (SCs) generate radial lamellipodia to sort and ensheath axons. This process requires controlled cytoskeletal remodeling, and we show that SC lamellipodia formation depends on the function of profilin 1 (Pfn1), an actin-binding protein involved in microfilament polymerization. Pfn1 is inhibited upon phosphorylation by ROCK, a downstream effector of the integrin linked kinase pathway. Thus, a dramatic reduction of radial lamellipodia formation is observed in SCs lacking integrin-linked kinase or treated with the Rho/ROCK activator lysophosphatidic acid. Knocking down Pfn1 expression by lentiviral-mediated shRNA delivery impairs SC lamellipodia formation in vitro, suggesting a direct role for this protein in PNS myelination. Indeed, SC-specific gene ablation of Pfn1 in mice led to profound radial sorting and myelination defects, confirming a central role for this protein in PNS development. Our data identify Pfn1 as a key effector of the integrin linked kinase/Rho/ROCK pathway. This pathway, acting in parallel with integrin β1/LCK/Rac1 and their effectors critically regulates SC lamellipodia formation, radial sorting and myelination during peripheral nervous system maturation.
authors.affiliation: Instituto de Biologia Molecular e Celular, 4150-180 Porto, Portugal.
authors.forename: Laura
authors.initials: L
authors.lastname: Montani
authors.forename: Tina
authors.initials: T
authors.lastname: Buerki-Thurnherr
authors.forename: Joana Paes
authors.initials: JP
authors.lastname: de Faria
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Pereira
authors.forename: Nuno G
authors.initials: NG
authors.lastname: Dias
authors.forename: Rui
authors.initials: R
authors.lastname: Fernandes
authors.forename: Ana F
authors.initials: AF
authors.lastname: Gonçalves
authors.forename: Attila
authors.initials: A
authors.lastname: Braun
authors.forename: Yves
authors.initials: Y
authors.lastname: Benninger
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Böttcher
authors.forename: Mercedes
authors.initials: M
authors.lastname: Costell
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: João B
authors.initials: JB
authors.lastname: Relvas
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000235:genetics; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics; D009479:Neuropeptides / Q000502:physiology; D010525:Peripheral Nerves / Q000502:physiology*; D017933:Peripheral Nervous System / Q000502:physiology*; D051304:Profilins / Q000502:physiology*; D011554:Pseudopodia / Q000235:genetics; D012583:Schwann Cells / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000502:physiology
chemical_list: D009479:Neuropeptides; C495739:Pfn1 protein, mouse; D051304:Profilins; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein
keywords: Mouse; Myelination; Profilin; Schwann cell