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

doi:10.1083/jcb.200206096

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, buttheir functions remain unknown. We found that keratinocyte ${alpha}$ 7nAChR controls homeostasis and terminal differentiation of epidermalkeratinocytes required for formation of the skin barrier. Theeffects of functional inactivation of ${alpha}$ 7 nAChR on keratinocytecell cycle progression, differentiation, and apoptosis werestudied in cell monolayers treated with ${alpha}$ -bungarotoxin or antisenseoligonucleotides and in the skin of Acra7 homozygous mice lacking ${alpha}$ 7 nAChR channels. Elimination of the ${alpha}$ 7 signaling pathway blockednicotine-induced influx of ⁴⁵Ca²⁺ and also inhibited terminaldifferentiation of these cells at the transcriptional and/ortranslational level. On the other hand, inhibition of the ${alpha}$ 7nAChR pathway favored cell cycle progression. In the epidermisof ${alpha}$ 7^-/- mice, the abnormalities in keratinocyte gene expressionwere associated with phenotypic changes characteristic of delayedepidermal turnover. The lack of ${alpha}$ 7 was associated with up-regulatedexpression 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 channelscontrols late stages of keratinocyte development in the epidermisby regulating expression of the cell cycle progression, apoptosis,and terminal differentiation genes and that these effects aremediated, at least in part, by alterations in transmembraneCa²⁺ influx.

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

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