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Flightless I (Flii) is an actin-remodeling protein that influences diverse processes including cell migration and gene transcription and links signal transduction with cytoskeletal regulation. Here, we show that Flii modulation of focal adhesions and filamentous actin stress fibers is Rac1-dependent. Using primary skin fibroblasts from Flii overexpressing (FliiTg/Tg), wild-type, and Flii deficient (Flii +/-) mice, we show that elevated expression of Flii increases stress fiber formation by impaired focal adhesion turnover and enhanced formation of fibrillar adhesions. Conversely, Flii knockdown increases the percentage of focal complex positive cells. We further show that a functional effect of Flii at both the cellular level and in in vivo mouse wounds is through inhibiting paxillin tyrosine phosphorylation and suppression of signaling proteins Src and p130Cas, both of which regulate adhesion signaling pathways. Flii is upregulated in response to wounding, and overexpression of Flii inhibits paxillin activity and reduces adhesion signaling by modulating the activity of the Rho family GTPases. Overexpression of constitutively active Rac1 GTPase restores the spreading ability of FliiTg/Tg fibroblasts and may explain the reduced adhesion, migration, and proliferation observed in FliiTg/Tg mice and their impaired wound healing, a process dependent on effective cellular motility and adhesion. Refereed/Peer-reviewed

Regeneration of cells, tissues, and organs has long captured the attention of researchers for its obvious potential benefits in biomedical applications. Although mammals are notoriously poor at regeneration compared with many lower-order species, the hair follicle, paradoxically a defining characteristic of mammals, is capable of regeneration following partial amputation. To investigate the role of a negative regulator of wound healing, flightless I (Flii), on hair follicle regeneration, the bulbar region of vibrissae from rats as well as strains of mice expressing low (Flii þ/ ), normal (Flii þ/þ), and high (FLIITg/Tg) levels of Flii were surgically amputated, and then allowed to regenerate in vivo. Macroscopic and histological assessment of the regeneration process revealed impaired or delayed regenerative potential in Flii þ/ follicles. Regenerated follicles expressing high levels of Flii (FLIITg/Tg) produced significantly longer terminal hair fibers. Immunohistochemical analysis was used to characterize the pattern of expression of Flii, as well as markers of hair follicle development and wound healing-associated factors during hair follicle regeneration. These studies confirmed that Flii appears to have a positive role in the regeneration of hair follicles, contrary to its negative influence on wound healing in skin. Refereed/Peer-reviewed