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PMID: 12093741 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Physiological and retinoid-induced proliferations of epidermis basal keratinocytes are differently controlled.

The EMBO journal ·Vol. 21 ·No. 13 ·2002-07-01 ·Pages 3402-13

Chapellier B, Mark M, Messaddeq N, Calléja C, Warot X, Brocard J, Gérard C, Li M, Metzger D, Ghyselinck NB, Chambon P

Abstract

To investigate the roles of retinoic acid (RA) receptors (RARs) in the physiology of epidermis that does not express RAR beta, conditional spatio-temporally controlled somatic mutagenesis was used to selectively ablate RAR alpha in keratinocytes of RAR gamma-null mice. Keratinocyte proliferation was maintained in adult mouse epidermis lacking both RAR alpha and RAR gamma, as well as in RAR beta-null mice. All RAR-mediated signalling pathways are therefore dispensable in epidermis for homeostatic keratinocyte renewal. However, topical treatment of mouse skin with selective retinoids indicated that RXR/RAR gamma heterodimers, in which RXR transcriptional activity was subordinated to that of its RAR gamma partner, were required for retinoid-induced epidermal hyperplasia, whereas RXR homodimers and RXR/RAR alpha heterodimers were not involved. RA-induced keratinocyte proliferation was studied in mutant mice in which RXR alpha, RXR alpha and RAR alpha, RAR gamma, or RXR alpha and RAR gamma genes were specifically disrupted in either basal or suprabasal keratinocytes. We demonstrate that the topical retinoid signal is transduced by RXR alpha/RAR gamma heterodimers in suprabasal keratinocytes, which, in turn, stimulate proliferation of basal keratinocytes via a paracrine signal that may be heparin-binding EGF-like growth factor.

MeSH Terms
Alleles Animals Cell Division/drug effects Crosses, Genetic Dimerization Epidermal Cells Epidermal Growth Factor/biosynthesis,genetics Epidermis/pathology Gene Targeting Heparin-binding EGF-like Growth Factor Homeostasis Hyperplasia Intercellular Signaling Peptides and Proteins Keratinocytes/cytology,drug effects Mice Mice, Knockout Mice, Transgenic Mutagenesis Paracrine Communication Protein Multimerization Receptors, Retinoic Acid/chemistry,deficiency,drug effects,physiology Retinoic Acid Receptor alpha Retinoid X Receptors Retinoids/pharmacology Tamoxifen/pharmacology Transcription Factors/chemistry,drug effects,physiology Transcription, Genetic Tretinoin/pharmacology
Chemicals
BMS 649 Hbegf protein, mouse Heparin-binding EGF-like Growth Factor Intercellular Signaling Peptides and Proteins Rara protein, mouse Receptors, Retinoic Acid Retinoic Acid Receptor alpha Retinoid X Receptors Retinoids Transcription Factors retinoic acid receptor gamma Tamoxifen Tretinoin Epidermal Growth Factor
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Chapellier Benoit
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France.
Mark Manuel
Messaddeq Nadia
Calléja Cécile
Warot Xavier
Brocard Jacques
Gérard Christelle
Li Mei
Metzger Daniel
Ghyselinck Norbert B
Chambon Pierre
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdf331
Published
2002-07-01
Pages
3402-13
Language
English
Region
England
NLM ID
8208664
PMCID
PMC125394
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/cdf331 PMC Full Text View journal details
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