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J Invest Dermatol. 2012 Oct;132(10):2350-9. doi: 10.1038/jid.2012.159. Epub 2012 May 24.

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

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  • 1Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California 94121, USA.


The calcium-sensing receptor (CaR) has 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 (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 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 than 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.

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