By screening N-ethyl-N-nitrosourea-mutagenized animals for alterations in rhythms of wheel-running activity, we identified a mouse mutation, after hours (Afh). The mutation, a Cys(358)Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes. Circadian transcriptional and translational oscillations are attenuated in Afh mice. The Afh allele significantly affected Per2 expression and delayed the rate of Cry protein degradation in Per2::Luciferase tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping.

Integrin expression is normally confined to the basal layer of the epidermis, but when epidermal homeostasis is perturbed, the receptors are also expressed by suprabasal, differentiating keratinocytes. We have used the involucrin promoter to express functional human integrin subunits alpha 2, alpha 5, and beta 1 in the suprabasal epidermal layers of transgenic mice. In mice expressing alpha 5 or beta 1 alone or alpha 2 beta 1 or alpha 5 beta 1 heterodimers, there were hair and whisker abnormalities and a failure of eyelid fusion. In addition, mice expressing beta 1 alone or in combination with alpha 2 or alpha 5 exhibited epidermal hyper-proliferation, perturbed keratinocyte differentiation, and skin inflammation, all of which are features of a common human skin disease, psoriasis.