Ablation of the Calcium-Sensing Receptor in Keratinocytes Impairs Epidermal Differentiation and Barrier Function

The calcium-sensing receptor (CaR) has an essential role in mediating Ca2+-induced keratinocyte differentiation in vitro. In this study, we generated keratinocyte-specific CaR knockout (EpidCaR−/−) mice to investigate the function of the CaR in epidermal development in vivo. EpidCaR−/− mice exhibited a delay in permeability barrier formation during embryonic development. Ion capture cytochemistry detected the loss of the epidermal Ca2+ gradient in the EpidCaR−/− mice. The expression of terminal differentiation markers and key enzymes mediating epidermal sphingolipid transport and processing in the EpidCaR−/− epidermis was significantly reduced. The EpidCaR−/− epidermis displayed a marked decrease in the number of lamellar bodies (LBs) and LB secretion, thinner lipid-bound cornified envelopes, and a defective permeability barrier. Consistent with in vivo results, epidermal keratinocytes cultured from EpidCaR−/− mice demonstrated abnormal Ca2+i handling and diminished differentiation. The impairment in epidermal differentiation and permeability barrier in EpidCaR−/− mice maintained on a low calcium (0.02%) diet is more profound and persistent with age than in EpidCaR−/− mice maintained on a normal calcium (1.3%) diet. Deleting CaR perturbs the epidermal Ca2+ gradient and impairs keratinocyte differentiation and permeability barrier homeostasis, indicating a key role for the CaR in normal epidermal development.