The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms.
Determining the roles of Rel/NF-kappaB 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(-/-) tnfalpha(-/-)), 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 G(1) 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.
Gugasyan
Raffi
R
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Voss
Anne
A
Varigos
George
G
Thomas
Tim
T
Grumont
Raelene J
RJ
Kaur
Pritinder
P
Grigoriadis
George
G
Gerondakis
Steve
S
D000367:Age Factors; D000818:Animals; D004622:Embryo, Mammalian; D018859:Hair Follicle / Q000254:growth & development; D006706:Homeostasis; D007249:Inflammation / Q000196:embryology / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012867:Skin / Q000737:chemistry / Q000196:embryology / Q000254:growth & development*; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology
D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha