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

J Invest Dermatol. 2012 Oct;132(10):2350-2359. doi: 10.1038/jid.2012.159. Epub 2012 May 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium, Dietary / pharmacology
  • Cell Differentiation / physiology*
  • Cell Membrane Permeability / drug effects
  • Cell Membrane Permeability / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Epidermal Cells*
  • Epidermis / metabolism
  • Homeostasis / physiology
  • Keratinocytes / cytology
  • Keratinocytes / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Models, Animal
  • Receptors, Calcium-Sensing / deficiency*
  • Receptors, Calcium-Sensing / genetics*
  • Receptors, Calcium-Sensing / metabolism
  • Skin Physiological Phenomena*
  • Sphingolipids / metabolism


  • Calcium, Dietary
  • Receptors, Calcium-Sensing
  • Sphingolipids
  • Calcium