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Vol. 19, Issue 4, 1462-1473, April 2008

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Impaired Hair Follicle Morphogenesis and Polarized Keratinocyte Movement upon Conditional Inactivation of Integrin-linked Kinase in the Epidermis

Kerry-Ann Nakrieko^*, Ian Welch, Holly Dupuis^*, Dawn Bryce^*, Agnieszka Pajak^*, René St. Arnaud, Shoukat Dedhar, Sudhir J. A. D'Souza^*, and Lina Dagnino^*,||

*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; Animal Care and Veterinary Services, University of Western Ontario, London, ON, N6A 5C1 Canada; Shriners Hospital and McGill University, Montreal, QC, H3G 1A6 Canada; Department of Biochemistry and BC Cancer Agency, University of British Columbia, Vancouver, BC, V6H 326 Canada; and ^||Department of Paediatrics, Child Health Research Institute and Lawson Health Research Institute, University of Western Ontario, London, ON, N6A 5C1 Canada

Submitted June 4, 2007; Revised January 9, 2008; Accepted January 17, 2008
Monitoring Editor: Asma Nusrat

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.

Address correspondence to: Lina Dagnino (ldagnino{at}uwo.ca) or Sudhir J. A. D'Souza (sjdsouza{at}uwo.ca)

Abbreviations used: BSA, bovine serum albumin; GFP, green fluorescent protein; GST, glutathione S-transferase; ILK, integrin-linked kinase; RFP, monomeric red fluorescent protein.