Impaired hair follicle morphogenesis and polarized keratinocyte movement upon conditional inactivation of integrin-linked kinase in the epidermis.
Integrin-linked kinase (ILK) is key for cell survival, migration, and adhesion, but little is known about its role in epidermal development and homeostasis in vivo. We generated mice with conditional inactivation of the Ilk gene in squamous epithelia. These mice die perinatally and exhibit skin blistering and severe defects in hair follicle morphogenesis, including greatly reduced follicle numbers, failure to progress beyond very early developmental stages, and pronounced defects in follicular keratinocyte proliferation. ILK-deficient epidermis shows abnormalities in adhesion to the basement membrane and in differentiation. ILK-deficient cultured keratinocytes fail to attach and spread efficiently and exhibit multiple abnormalities in actin cytoskeletal organization. Ilk gene inactivation in cultured keratinocytes causes impaired ability to form stable lamellipodia, to directionally migrate, and to polarize. These defects are accompanied by abnormal distribution of active Cdc42 to cell protrusions, as well as reduced activation of Rac1 upon induction of cell migration in scraped keratinocyte monolayers. Significantly, alterations in cell spreading and forward movement in single cells can be rescued by expression of constitutively active Rac1 or RhoG. Our studies underscore a central and distinct role for ILK in hair follicle development and in polarized cell movements, two key aspects of epithelial morphogenesis and function.
Nakrieko
Kerry-Ann
KA
Department of Physiology and Pharmacology, and Regulatory Biology and Functional Genomics Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, ON, N6A 5C1, Canada.
Welch
Ian
I
Dupuis
Holly
H
Bryce
Dawn
D
Pajak
Agnieszka
A
St Arnaud
René
R
Dedhar
Shoukat
S
D'Souza
Sudhir J A
SJ
Dagnino
Lina
L
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D016764:Cell Polarity; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D018859:Hair Follicle / Q000201:enzymology / Q000254:growth & development*; D015603:Keratinocytes / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009479:Neuropeptides / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D000099200:Scaffold Protein ILK
D000199:Actins; D009479:Neuropeptides; D017346:Protein Serine-Threonine Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000099200:Scaffold Protein ILK; C484602:Rac1 protein, mouse