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

Abstract

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 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 (LBs) and LB 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 Ca2+ 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 than in Epid CaR-/- 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. © 2012 The Society for Investigative Dermatology.