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Molecular and Cellular Biology, July 2004, p. 5733-5745, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5733-5745.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Transcription Factors c-rel and RelA Control Epidermal Development and Homeostasis in Embryonic and Adult Skin via Distinct Mechanisms

Raffi Gugasyan,1 Anne Voss,1 George Varigos,2 Tim Thomas,1 Raelene J. Grumont,1 Pritinder Kaur,3 George Grigoriadis,1 and Steve Gerondakis1*

The Walter and Eliza Hall Institute of Medical Research,1 Royal Melbourne Hospital, Parkville, Victoria 3050,2 Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002, Australia3

Received 11 January 2004/ Returned for modification 25 February 2004/ Accepted 19 April 2004

Determining the roles of Rel/NF-{kappa}B transcription factors in mouse skin development with loss-of-function mutants has been limited by redundancy among these proteins and by embryonic lethality associated with the absence of RelA. Using mice lacking RelA and c-rel, which survive throughout embryogenesis on a tumor necrosis factor alpha (TNF-{alpha})-deficient background (rela–/– c-rel–/– tnf{alpha}–/–), we show that c-rel and RelA are required for normal epidermal development. Although mutant fetuses fail to form tylotrich hair and have a thinner epidermis, mutant keratinocyte progenitors undergo terminal differentiation to form an outer cornified layer. Mutant basal keratinocytes are abnormally small, exhibit a delay in G1 progression, and fail to form keratinocyte colonies in culture. In contrast to the reduced proliferation of mutant keratinocytes during embryogenesis, skin grafting experiments revealed that the mutant epidermis develops a TNF-{alpha}-dependent hyperproliferative condition. Collectively, our findings indicate that RelA and c-rel control the development of the epidermis and associated appendages during embryogenesis and regulate epidermal homeostasis in a postnatal environment through the suppression of innate immune-mediated inflammation.

* Corresponding author. Mailing address: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Phone: 61393452542. Fax: 61393470852. E-mail: gerondakis{at}wehi.edu.au.

Molecular and Cellular Biology, July 2004, p. 5733-5745, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5733-5745.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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