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.
Highlights
Epithelial differentiation and stratification are essential for normal homeostasis, and disruption of these processes leads to both injury and cancer
Using primary keratinocytes in organotypic culture, we show that loss of Krüppel-like factor 4 (KLF4) impairs squamous epithelial differentiation and demonstrate functionally that WNT5A rescues the effects of KLF4 loss on differentiation and stratification
In esophageal epithelia of control mice, WNT5A localized to regions of cellular differentiation (Fig. 1A), a pattern of expression that overlapped with the expression domain of KLF4 (Figure S1A)[16,34]; WNT5A and KLF4 co-localized in primary esophageal keratinocytes in culture (Figure S1B)
Summary
Epithelial differentiation and stratification are essential for normal homeostasis, and disruption of these processes leads to both injury and cancer. Esophageal cancer is currently the 6th most common cause of cancer death in the world, and more than 90% of these esophageal cancers are squamous cell cancers, arising within the stratified squamous epithelial cells that normally line the esophagus[3,6]. Klf[4] deletion leads to loss of barrier function and defective late-stage differentiation, with early lethality by postnatal day 1 due to these barrier defects[14], and in the esophagus, Klf[4] ablation results in delayed differentiation, abnormal stratification, and the development of precancerous squamous cell dysplasia[16]. Klf[4] loss promotes skin carcinogenesis in mice[19] Taken together, these data demonstrate a requirement of KLF4 for squamous epithelial differentiation and the relevance of KLF4 to human diseases[20,21]
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