The epidermal differentiation-associated Grainyhead gene Get1/Grhl3 also regulates urothelial differentiation.
Skin and bladder epithelia form effective permeability barriers through the activation of distinct differentiation gene programs. Using a genome-wide gene-expression study, we identified transcriptional regulators whose expression correlates highly with that of differentiation markers in both the bladder and skin, including the Grainyhead factor Get1/Grhl3, which is already known to be important for epidermal barrier formation. In the bladder, Get1 is most highly expressed in the differentiated umbrella cells and its mutation in mice leads to a defective bladder epithelial barrier formation due to the failure of apical membrane specialization. Genes encoding components of the specialized urothelial membrane, the uroplakins, were downregulated in Get1(-/-) mice. At least one of these genes, uroplakin II, is a direct target of Get1. The urothelial-specific activation of the uroplakin II gene is due to selective binding of Get1 to the uroplakin II promoter in urothelial cells, which is most likely regulated by histone modifications. These results show a crucial role for Get1 in urothelial differentiation and barrier formation.
Yu
Zhengquan
Z
Department of Medicine, University of California, Irvine, CA 92697-4030, USA.
Mannik
Jaana
J
Soto
Amelia
A
Lin
Kevin K
KK
Andersen
Bogi
B
D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008751:Methylene Blue / Q000378:metabolism; D051379:Mice; D010539:Permeability; D012867:Skin / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001743:Urinary Bladder / Q000166:cytology* / Q000378:metabolism*; D060170:Uroplakin II; D019459:Urothelium / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure
D004268:DNA-Binding Proteins; C499942:Grhl3 protein, mouse; D008565:Membrane Proteins; D014157:Transcription Factors; C554659:Upk2 protein, mouse; D060170:Uroplakin II; D008751:Methylene Blue