Hair cycle and wound healing in mice with a keratinocyte-restricted deletion of FAK

Abstract

Focal adhesion kinase (FAK) is a critical component in transducing signals downstream of both integrins and growth factor receptors. To determine how the loss of FAK affects the epidermis in vivo, we have generated a mouse model with a keratinocyte-restricted deletion of fak (FAK K5 KO mice). FAK K5 KO mice displayed three major phenotypes -irregularities of hair cycle, sebaceous glands hypoplasia, and a thinner epidermis -pointing to defects in the proliferative capacity of multipotent stem cells found in the bulge. FAK-null keratinocytes in conventional primary culture undergo massive apoptosis hindering further analyses, whereas the defects observed in vivo do not shorten the mouse lifespan. These results suggest that the structure and the signaling environment of the native tissue may overcome the lack of signaling through FAK. Our findings point to the importance of in vivo and threedimensional in vitro models in analyses of cell migration, proliferation, and survival. Surprisingly, the difference between FAK loxP/ þ and FAK K5 KO mice in wound closure was not statistically significant, suggesting that in vivo loss of FAK does not affect migration/proliferation of basal keratinocytes in the same way as it affects multipotent stem cells of the skin.

Focal adhesion kinase signaling pathways regulate the osteogenic differentiation of human mesenchymal stem cells

“…For example, hundreds of papers report that FAK plays a significant a role in cell migration in vitro, and this is now well accepted. However, there are no differences in healing of skin wounds in either keratin 14-Cre [41] or keratin 5-Cre [42] keratinocyte-specific FAK knockout mice. Moreover, FAK-null keratinocytes do not survive in vitro, but are quite viable in these animals.…”

FAK engages multiple pathways to maintain survival of fibroblasts and epithelia – differential roles for paxillin and p130Cas

“…For example, FAK deletion in keratinocytes resulted in defects in epidermal thickness and hair growth, but there were no apoptosis defects in vivo. However, keratinocytes isolated from these animals died rapidly in vitro, indicating that FAK was required to support survival under certain conditions (Essayem et al, 2006). By contrast, deletion of FAK in endothelial cells resulted in an increase in apoptosis in vivo, leading to lethality before day 10.5 due to extensive haemorrhaging (Braren et al, 2006).…”

“…Other studies have shown that disrupting FAK signalling using anti-FAK antibodies, antisense oligonucleotides, or the expression of dominant-negative FAK, induces apoptosis in adherent cells (Gilmore et al, 2000;Hungerford et al, 1996;Ilic et al, 1998;Xu et al, 1996;Xu et al, 1998). Moreover, genetic deletion of FAK sensitises keratinocytes and endothelial cells to apoptosis in vivo (Braren et al, 2006;Essayem et al, 2006). Disruption of FAK signalling not only has effects in normal cells but is also implicated in tumour progression.…”

Mammary Epithelial-Specific Disruption of Focal Adhesion Kinase Retards Tumor Formation and Metastasis in a Transgenic Mouse Model of Human Breast Cancer

“…Use of antibodies specific for the N-and Cterminal regions of FAK confirmed the absence of truncated FAK products or changes in FRNK expression (data not shown), consistent with previous reports using floxed-FAK mice. 50,52,63 The remaining presence of FAK protein in the FAK flox/flox /MMTV-Cre tissue was likely attributable to cells in the stromal and vascular compartments that do not express Cre recombinase. 10,52 Therefore, to confirm that FAK was being excised efficiently in the epithelial population, we purified primary mammary epithelial cells from FAK flox/flox /Cre-negative mice and infected them with an adenovirus expressing Cre recombinase and GFP (ad-Cre-GFP).…”