Ablation of the calcium-sensing receptor in keratinocytes impairs epidermal differentiation and barrier function

The calcium-sensing receptor (CaR) plays an essential role in mediating Ca(2+)-induced keratinocyte differentiation in vitro. In this study, we generated keratinocyte-specific CaR knockout ((Epid)CaR-/-) mice to investigate the function of the CaR in epidermal development in vivo. (Epid)CaR-/- mice exhibited a delay in permeability barrier formation during embryonic development. Ion capture cytochemistry detected the loss of the epidermal Ca(2+) gradient in the (Epid)CaR-/- mice. The expression of terminal differentiation markers and key enzymes mediating epidermal sphingolipid transport and processing in the (Epid)CaR-/- epidermis was significantly reduced. The (Epid)CaR-/- epidermis displayed a marked decrease in the number of lamellar bodies and lamellar body secretion, thinner lipid-bound cornified envelopes and a defective permeability barrier. Consistent with in vivo results, epidermal keratinocytes cultured from (Epid)CaR-/- mice demonstrated abnormal Ca(2+)(I) handling and diminished differentiation. The impairment in epidermal differentiation and permeability barrier in (Epid)CaR-/- mice maintained on a low calcium (0.02%) diet is more profound and persistent with age then in (Epid)CaR-/- mice maintained on a normal calcium (1.3%) diet. Deleting CaR perturbs the epidermal Ca(2+) gradient and impairs keratinocyte differentiation and permeability barrier homeostasis, indicating a key role for the CaR in normal epidermal development.