Yap Tunes Airway Epithelial Size and Architecture by Regulating the Identity, Maintenance, and Self-Renewal of Stem Cells

Abstract

SUMMARY Our understanding of how stem cells are regulated to maintain appropriate tissue size and architecture is incomplete. We show that Yap is required for the actual maintenance of an adult mammalian stem cell. Without Yap, adult airway basal stem cells are lost through their unrestrained differentiation, resulting in the simplification of a pseudostratified epithelium into a columnar one. Conversely, Yap overexpression increases stem cell self-renewal and blocks terminal differentiation, resulting in epithelial hyperplasia and stratification. Yap overexpression in differentiated secretory cells causes them to partially reprogram and adopt a stem cell-like identity. In contrast, Yap knockdown prevents the dedifferentiation of secretory cells into stem cells. We then show that Yap functionally interacts with p63, the cardinal transcription factor associated with myriad epithelial basal stem cells. In aggregate, we show that Yap regulates all of the cardinal behaviors of airway epithelial stem cells and in so doing determines epithelial architecture.

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

“…Conditional deletion of YAP led to disruption of branching morphogenesis, with expansion of distal epithelial progenitors and reciprocal reduction of proximal Sox2-expressing progenitors and impaired adult airway epithelial cell differentiation (56). Nuclear YAP promoted airway basal cell identity, whereas YAP overexpression blocked basal cell terminal differentiation, and YAP overexpression in differentiated secretory cells promoted a stem cell-like identity (55). Activation of YAP in lung airway epithelium following deletion of Mst1/2 under control of the Scgb1a1 promoter inhibited lung sacculation and maturation and resulted in club cell hyperplasia with increased bronchiolar epithelial cell proliferation and decreased differentiation (57).…”

“…In the lung, YAP is required for correct proximal-distal patterning of the airway and regulation of airway epithelial cell fate (55,56). Conditional deletion of YAP led to disruption of branching morphogenesis, with expansion of distal epithelial progenitors and reciprocal reduction of proximal Sox2-expressing progenitors and impaired adult airway epithelial cell differentiation (56).…”

Integrin signalling regulates YAP and TAZ to control skin homeostasis

“…The function of YAP family co-activators was first discovered by Drosophila genetics, where the sole YAP homologue Yorkie (Yki) was found to be necessary and sufficient to promote cell proliferation and tissue overgrowth in epithelia (Huang et al, 2005). Subsequent genetic experiments in mice showed that ectopic expression of YAP (also known as YAP1) was sufficient to drive cell proliferation in liver, intestine, bronchus and skin Camargo et al, 2007;Dong et al, 2007;Schlegelmilch et al, 2011;Zhang et al, 2011a;Zhao et al, 2014). Surprisingly, YAP knockout mice have mild phenotypes, although they are deficient in proliferative repair of the intestine and resistant to intestinal tumour formation (Azzolin et al, 2014;Cai et al, 2010), as well as showing reduced bronchial stem cells (Zhao et al, 2014) and kidney defects (Reginensi et al, 2015).…”

“…Subsequent genetic experiments in mice showed that ectopic expression of YAP (also known as YAP1) was sufficient to drive cell proliferation in liver, intestine, bronchus and skin Camargo et al, 2007;Dong et al, 2007;Schlegelmilch et al, 2011;Zhang et al, 2011a;Zhao et al, 2014). Surprisingly, YAP knockout mice have mild phenotypes, although they are deficient in proliferative repair of the intestine and resistant to intestinal tumour formation (Azzolin et al, 2014;Cai et al, 2010), as well as showing reduced bronchial stem cells (Zhao et al, 2014) and kidney defects (Reginensi et al, 2015). An important and widespread physiological role for YAP in mice might be obscured by the possibility of redundancy between YAP and TAZ (also known as WWTR1) a second mammalian family member that is highly similar in both sequence and function.…”

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

“…In contrast, expression of IkB-a results in strong induction of p63 expression, indicating that p63 is, indeed, negatively regulated by NFkB (27,28). In addition, some crosstalk between p63 and the Hippo pathway has been discovered recently (25,29), for example, DNp63 directly interacts with the Hippo effector YAP and is a mediator of YAP function in the epithelium of lung airways (30). p63 coamplified with ACTL6A in SCC to drive YAP activity, which resulted in regeneration, proliferation, and poor prognosis (31).…”