title: Two Ancient Gene Families Are Critical for Maintenance of the Mammalian Skin Barrier in Postnatal Life.
abstract: The skin barrier is critical for mammalian survival in the terrestrial environment, affording protection against fluid loss, microbes, toxins, and UV exposure. Many genes indispensable for barrier formation in the embryo have been identified, but loss of these genes in adult mice does not induce barrier regression. We describe a complex regulatory network centered on two ancient gene families, the grainyhead-like (Grhl) transcription factors and the protein cross-linking enzymes (tissue transglutaminases [Tgms]), which are essential for skin permeability barrier maintenance in adult mice. Embryonic deletion of Grhl3 induces loss of Tgm1 expression, which disrupts the cornified envelope, thus preventing permeability barrier formation leading to neonatal death. However, gene deletion of Grhl3 in adult mice does not disrupt the preformed barrier, with cornified envelope integrity maintained by Grhl1 and Tgm5, which are up-regulated in response to postnatal loss of Grhl3. Concomitant deletion of both Grhl factors in adult mice induced loss of Tgm1 and Tgm5 expression, perturbation of the cornified envelope, and complete permeability barrier regression that was incompatible with life. These findings define the molecular safeguards for barrier function that accompany the transition from intrauterine to terrestrial life.
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Cangkrama
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia.
authors.forename: Charbel
authors.initials: C
authors.lastname: Darido
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia.
authors.forename: Smitha R
authors.initials: SR
authors.lastname: Georgy
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia.
authors.forename: Darren
authors.initials: D
authors.lastname: Partridge
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia.
authors.forename: Alana
authors.initials: A
authors.lastname: Auden
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia.
authors.forename: Seema
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Laboratory of Signal Transduction, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wilanowski
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia; Alfred Hospital, Prahran, Australia. Electronic address: stephen.jane@monash.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Jane
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008322:Mammals; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D005810:Multigene Family; D010539:Permeability; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000196:embryology* / Q000254:growth & development*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C528337:Grhl1 protein, mouse; C499942:Grhl3 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D007633:Keratins; D011503:Transglutaminases; C105804:transglutaminase 1