Epidermal expression of the full-length extracellular calcium-sensing receptor is required for normal keratinocyte differentiation.
The importance of the extracellular calcium-sensing receptor (CaR) in the stringent control of extracellular Ca(2+) concentration is well established. However, the presence of CaR in tissues not directly involved in regulating mineral ion homeostasis such as the epidermis suggests a role for CaR in other cellular functions. Although extracellular Ca(2+) regulates the differentiation of epidermal keratinocytes, the role of CaR in this process in the epidermis is not fully understood. In this study we showed using in situ hybridization and immunohistochemistry that CaR is expressed in suprabasal keratinocytes of the mammalian epidermis. We then evaluated the changes in epidermal keratinocyte morphology and differentiation in Casr(-/-) mice lacking the full-length CaR. These mice show increased expression of an alternatively spliced form of CaR which lacks acute Ca(2+)-signaling properties. The absence of the full-length CaR in the epidermis resulted in ultrastructural changes (abnormal keratohyalin granule formation and precocious lamellar body secretion) in the terminally differentiated granular keratinocytes. Furthermore, the expression of both mRNA and protein for the calcium inducible keratinocyte differentiation markers, filaggrin and loricrin, were down-regulated in the epidermis of Casr(-/-) mice, whereas the number of proliferating cells were increased even though the calcium gradient within the epidermis was enhanced. Our results demonstrate that the epidermal expression of the full-length CaR is required for the normal terminal differentiation of keratinocytes.
Department of Dermatology, Veterans Affairs Medical Center and the University of California, San Francisco School of Medicine, San Francisco, California 94121, USA.
Laszlo
L
Komuves
Yuko
Y
Oda
Chia-Ling
CL
Tu
Wen Han
WH
Chang
Chrystal L
CL
Ho-Pao
Theodora
T
Mauro
Daniel D
DD
Bikle
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; C473605:extracellular calcium cation-sensing receptor, rat; D002118:Calcium