title: KLF4 transcriptionally activates non-canonical WNT5A to control epithelial stratification.
abstract: Epithelial differentiation and stratification are essential for normal homeostasis, and disruption of these processes leads to both injury and cancer. The zinc-finger transciption factor KLF4 is a key driver of epithelial differentiation, yet the mechanisms and targets by which KLF4 controls differentiation are not well understood. Here, we define WNT5A, a non-canonical Wnt ligand implicated in epithelial differentiation, repair, and cancer, as a direct transcriptional target that is activated by KLF4 in squamous epithelial cells. Further, we demonstrate functionally that WNT5A mediates KLF4 control of epithelial differentiation and stratification, as treatment of keratinocytes with WNT5A rescues defective epithelial stratification resulting from KLF4 loss. Finally, we show that the small GTPase CDC42 is regulated by KLF4 in a WNT5A dependent manner. As such, we delineate a novel pathway for epithelial differentiation and stratification and define potential therapeutic targets for epithelial diseases.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA.
authors.forename: Marie-Pier
authors.initials: MP
authors.lastname: Tetreault
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weinblatt
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA.
authors.forename: Khvaramze
authors.initials: K
authors.lastname: Shaverdashvili
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA.
authors.forename: Yizeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Katz
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D000071818:Wnt-5a Protein; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; C000626589:CDC42 protein, human; D020764:cdc42 GTP-Binding Protein