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Published online 21 October 2002. doi:10.1083/jcb.200206096
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© The Rockefeller University Press, 0021-9525/2002/10/325 $5.00
The Journal of Cell Biology, Volume 159, Number 2, 325-336

Article

 Central role of {alpha}7 nicotinic receptor in differentiation of the stratified squamous epithelium

Juan Arredondo1, Vu Thuong Nguyen1, Alexander I. Chernyavsky1, Dani Bercovich2,3, Avi Orr-Urtreger4, Wolfgang Kummer5, Katrin Lips5, Douglas E. Vetter6 and Sergei A. Grando1

1 Department of Dermatology, University of California, Davis, Sacramento, CA 95817
2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
3 Department of Molecular Genetics, Migal-Galilee Technology Center
4 Genetic Institute, Tel Aviv Sourasky Medical Center, and Tel Aviv University, 64239 Tel Aviv, Israel
5 Institut für Anatomie und Zellbiologie, Justus-Liebig-Universität Giessen, Giessen D-35385, Germany
6 Neuroscience Department, Tufts University, School of Medicine, Boston, MA 02111

Address correspondence to Sergei A. Grando, Dept. of Dermatology, University of California, Davis, UC Davis Medical Center, 4860 Y Street, #3400, Sacramento, CA 95817. Tel.: (916) 734-6057. Fax: (916) 734-6793. E-mail: sagrando{at}ucdavis.edu

Several ganglionic nicotinic acetylcholine receptor (nAChR) types are abundantly expressed in nonneuronal locations, but their functions remain unknown. We found that keratinocyte {alpha}7 nAChR controls homeostasis and terminal differentiation of epidermal keratinocytes required for formation of the skin barrier. The effects of functional inactivation of {alpha}7 nAChR on keratinocyte cell cycle progression, differentiation, and apoptosis were studied in cell monolayers treated with {alpha}-bungarotoxin or antisense oligonucleotides and in the skin of Acra7 homozygous mice lacking {alpha}7 nAChR channels. Elimination of the {alpha}7 signaling pathway blocked nicotine-induced influx of 45Ca2+ and also inhibited terminal differentiation of these cells at the transcriptional and/or translational level. On the other hand, inhibition of the {alpha}7 nAChR pathway favored cell cycle progression. In the epidermis of {alpha}7-/- mice, the abnormalities in keratinocyte gene expression were associated with phenotypic changes characteristic of delayed epidermal turnover. The lack of {alpha}7 was associated with up-regulated expression of the {alpha}3 containing nAChR channels that lack {alpha}5 subunit, and both homomeric {alpha}9- and heteromeric {alpha}9{alpha}10-made nAChRs. Thus, this study demonstrates that ACh signaling through {alpha}7 nAChR channels controls late stages of keratinocyte development in the epidermis by regulating expression of the cell cycle progression, apoptosis, and terminal differentiation genes and that these effects are mediated, at least in part, by alterations in transmembrane Ca2+ influx.

Key Words: cell cycle; differentiation; {alpha}7 acetylcholine receptor; epidermis; knockout mouse


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