Lipid defect underlies selective skin barrier impairment of an epidermal-specific deletion of Gata-3.
Skin lies at the interface between the complex physiology of the body and the external environment. This essential epidermal barrier, composed of cornified proteins encased in lipids, prevents both water loss and entry of infectious or toxic substances. We uncover that the transcription factor GATA-3 is required to establish the epidermal barrier and survive in the ex utero environment. Analysis of Gata-3 mutant transcriptional profiles at three critical developmental stages identifies a specific defect in lipid biosynthesis and a delay in differentiation. Genomic analysis identifies highly conserved GATA-3 binding sites bound in vivo by GATA-3 in the first intron of the lipid acyltransferase gene AGPAT5. Skin from both Gata-3-/- and previously characterized barrier-deficient Kruppel-like factor 4-/- newborns up-regulate antimicrobial peptides, effectors of innate immunity. Comparison of these animal models illustrates how impairment of the skin barrier by two genetically distinct mechanisms leads to innate immune responses, as observed in the common human skin disorders psoriasis and atopic dermatitis.
de Guzman Strong
Cristina
C
National Human Genome Research Institute and 2National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Wertz
Philip W
PW
Wang
Chenwei
C
Yang
Fan
F
Meltzer
Paul S
PS
Andl
Thomas
T
Millar
Sarah E
SE
Ho
I-Cheng
IC
Pai
Sung-Yun
SY
Segre
Julia A
JA
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000196:embryology; D047108:Embryonic Development; D004817:Epidermis / Q000002:abnormalities* / Q000196:embryology / Q000503:physiopathology* / Q000648:ultrastructure; D005091:Exons / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D007113:Immunity, Innate / Q000276:immunology; D007438:Introns / Q000235:genetics; D053535:Keratin-13 / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D050356:Lipid Metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D016038:Skin Transplantation; D014158:Transcription, Genetic
D050990:GATA3 Transcription Factor; C000715467:KLF4 protein, human; D053535:Keratin-13; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors