The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4.
Defective permeability barrier is an important feature of many skin diseases and causes mortality in premature infants. To investigate the control of barrier formation, we characterized the epidermally expressed Grainyhead-like epithelial transactivator (Get-1)/Grhl3, a conserved mammalian homologue of Grainyhead, which plays important roles in cuticle development in Drosophila. Get-1 interacts with the LIM-only protein LMO4, which is co-expressed in the developing mammalian epidermis. The epidermis of Get-1(-/-) mice showed a severe barrier function defect associated with impaired differentiation of the epidermis, including defects of the stratum corneum, extracellular lipid composition and cell adhesion in the granular layer. The Get-1 mutation affects multiple genes linked to terminal differentiation and barrier function, including most genes of the epidermal differentiation complex. Get-1 therefore directly or indirectly regulates a broad array of epidermal differentiation genes encoding structural proteins, lipid metabolizing enzymes and cell adhesion molecules. Although deletion of the LMO4 gene had no overt consequences for epidermal development, the epidermal terminal differentiation defect in mice deleted for both Get-1 and LMO4 is much more severe than in Get-1(-/-) mice with striking impairment of stratum corneum formation. These findings indicate that the Get-1 and LMO4 genes interact functionally to regulate epidermal terminal differentiation.
Yu
Zhengquan
Z
Departments of Medicine and Biological Chemistry, University of California, Irvine, CA 92697-4030, USA.
Lin
Kevin K
KK
Bhandari
Ambica
A
Spencer
Joel A
JA
Xu
Xiaoman
X
Wang
Ning
N
Lu
Zhongxian
Z
Gill
Gordon N
GN
Roop
Dennis R
DR
Wertz
Philip
P
Andersen
Bogi
B
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation; D062445:Claudin-1; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology* / Q000648:ultrastructure; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D062793:Occludin; D010539:Permeability; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013270:Stomach / Q000166:cytology / Q000473:pathology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C568108:CLDN1 protein, human; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D004268:DNA-Binding Proteins; C499942:Grhl3 protein, mouse; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D008055:Lipids; C491976:Lmo4 protein, mouse; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors