title: FAK is required for Schwann cell spreading on immature basal lamina to coordinate the radial sorting of peripheral axons with myelination.
abstract: Without Focal Adhesion Kinase (FAK), developing murine Schwann cells (SCs) proliferate poorly, sort axons inefficiently, and cannot myelinate peripheral nerves. Here we show that FAK is required for the development of SCs when their basal lamina (BL) is fragmentary, but not when it is mature in vivo. Mutant SCs fail to spread on fragmentary BL during development in vivo, and this is phenocopied by SCs lacking functional FAK on low laminin (LN) in vitro. Furthermore, SCs without functional FAK initiate differentiation prematurely, both in vivo and in vitro. In contrast to their behavior on high levels of LN, SCs lacking functional FAK grown on low LN display reduced spreading, proliferation, and indicators of contractility (i.e., stress fibers, arcs, and focal adhesions) and are primed to differentiate. Growth of SCs lacking functional FAK on increasing LN concentrations in vitro revealed that differentiation is not regulated by G1 arrest but rather by cell spreading and the level of contractile actomyosin. The importance of FAK as a critical regulator of the specific response of developing SCs to fragmentary BL was supported by the ability of adult FAK mutant SCs to remyelinate demyelinated adult nerves on mature BL in vivo. We conclude that FAK promotes the spreading and actomyosin contractility of immature SCs on fragmentary BL, thus maintaining their proliferation, and preventing differentiation until they reach high density, thereby promoting radial sorting. Hence, FAK has a critical role in the response of SCs to limiting BL by promoting proliferation and preventing premature SC differentiation.
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Grove
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom Peter.Brophy@ed.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001485:Basement Membrane / Q000503:physiopathology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000473:pathology*; D012583:Schwann Cells / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000473:pathology*
chemical_list: C493961:Cdkn1b protein, mouse; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571338:Cnp protein, mouse
keywords: FAK; Schwann cell; basal lamina; myelination