title: 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 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.
authors.affiliation: Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, USA. Electronic address: chia-ling.tu@ucsf.edu.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Tu
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Crumrine
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Mao-Qiang
authors.initials: MQ
authors.lastname: Man
authors.affiliation: Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
authors.affiliation: Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Hashem
authors.initials: H
authors.lastname: Elalieh
authors.affiliation: Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: You
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002136:Calcium, Dietary / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D023421:Models, Animal; D044169:Receptors, Calcium-Sensing / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D012879:Skin Physiological Phenomena; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D002136:Calcium, Dietary; D044169:Receptors, Calcium-Sensing; D013107:Sphingolipids; D002118:Calcium