Loss of calcineurin Aalpha alters keratinocyte survival and differentiation

Calcineurin is a serine/threonine phosphatase that is inhibited by the immunosuppressive drugs cyclosporine and FK506. Although calcineurin has been extensively studied in immune cells, less is known about calcineurin in other systems. There are two primary isoforms of the catalytic subunit of calcineurin, and mice have been created that lack either the alpha isoform (calcineurin A (CnA)alpha(-/-)) or the beta isoform (CnAbeta(-/-)). In this study, we examined the epidermis of CnAalpha(-/-) mice at birth and 4 weeks of age. Histological analyses revealed an attenuation of cells in the stratum spinosum of CnAalpha(-/-) mice. There was no significant difference in proliferation in the epidermis of CnAalpha(-/-) sections, but TUNEL assay revealed increased cell death in the supra-basal layers. Interestingly, the calcineurin substrate nuclear factor of activated T cells (NFATc) was highly expressed in the nucleus of basal epidermal cells in wild-type (WT) mice but was cytoplasmic in CnAalpha(-/-) mice, consistent with a loss of calcineurin activity. Moreover, NFATc activity was decreased in the epidermis of null mice compared with that in WT littermates. Finally, immunohistochemical staining revealed supra-basal expression of keratin 14 and decreased expression of differentiation-associated keratin 10 and involucrin. These findings suggest that calcineurin Aalpha activity is required for the normal differentiation and survival of epidermal cells.