title: Integrin-linked kinase regulates process extension in oligodendrocytes via control of actin cytoskeletal dynamics.
abstract: Integrin-linked kinase (ILK) is a major structural adaptor protein governing signaling complex formation and cytoskeletal dynamics. Here, through the use of conditional knock-out mice, we demonstrate a requirement for ILK in oligodendrocyte differentiation and axonal myelination in vivo. In conjunction, ILK-deficient primary oligodendrocytes are defined by a failure in process extension and an inability to form myelin membrane upon axonal contact. Surprisingly, phosphorylation of the canonical downstream targets Akt and GSK3β is unaffected following ILK loss. Rather, the defects are due in part to actin cytoskeleton dysregulation with a correspondent increase in active RhoA levels. Morphological rescue is possible following Rho kinase inhibition in an oligodendrocyte subset. Furthermore, phenotypic severity correlates with environmental complexity; oligodendrocytes are severely malformed in vitro (a relatively simple environment), but undergo phenotypic recovery in the context of the whole animal. Together, our work demonstrates ILK as necessary for normal oligodendrocyte development, reinforces its role as a bridge between the actin cytoskeleton and cell membrane, and highlights the overarching compensatory capacity of oligodendrocytes in response to cellular milieu.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: O'Meara
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Michalski
authors.forename: Carrie
authors.initials: C
authors.lastname: Anderson
authors.forename: Kunal
authors.initials: K
authors.lastname: Bhanot
authors.forename: Peter
authors.initials: P
authors.lastname: Rippstein
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D056004:Molecular Dynamics Simulation; D009836:Oligodendroglia / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000099200:Scaffold Protein ILK
chemical_list: D000199:Actins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK