Yap and Taz are required for Ret-dependent urinary tract morphogenesis

Abstract

Despite the high occurrence of congenital abnormalities of the lower urinary tract in humans, the molecular, cellular and morphological aspects of their development are still poorly understood. Here, we use a conditional knockout approach to inactivate within the nephric duct (ND) lineage the two effectors of the Hippo pathway, Yap and Taz. Deletion of Yap leads to hydronephrotic kidneys with blind-ending megaureters at birth. In Yap mutants, the ND successfully migrates towards, and contacts, the cloaca. However, close analysis reveals that the tip of the Yap −/− ND forms an aberrant connection with the cloaca and does not properly insert into the cloaca, leading to later detachment of the ND from the cloaca. Taz deletion from the ND does not cause any defect, but analysis of Yap −/− ;Taz −/− NDs indicates that both genes play partially redundant roles in ureterovesical junction formation. Aspects of the Yap −/− phenotype resemble hypersensitivity to RET signaling, including excess budding of the ND, increased phospho-ERK and increased expression of Crlf1, Sprouty1, Etv4 and Etv5. Importantly, the Yap ND−/− ND phenotype can be largely rescued by reducing Ret gene dosage. Taken together, these results suggest that disrupting Yap/Taz activities enhances Ret pathway activity and contributes to pathogenesis of lower urinary tract defects in human infants.

Hippo signaling in the kidney: the good and the bad

“…Taz NDϪ/Ϫ kidneys develop nor- mally, suggesting that YAP expression is sufficient in the absence of TAZ. However, silencing of Taz in Yap NDϪ/Ϫ mice severely worsens the phenotype, with kidneys being dysplastic, showing no ureters at E18.5, aberrant branching morphogenesis, blind-ending NDs, a defective ND-cloaca connection, and markedly increased apoptosis (48). These findings highlight the crucial role YAP and TAZ play in lower urinary tract development and lay the groundwork for further diagnostic, mechanistic, and therapeutic approaches to CAKUT.…”

“…Astonishingly, Ret mutations are present in 30% of fetuses with bilateral or unilateral renal agenesis (59). Silencing of Yap in the ND in mice results in death within 24 h of birth due to severe anomalies of the kidney and urinary tract, including hydroureter and nephrosis (48). This phenotype mimics hyperactive Ret signaling accompanied by increased expression of Ret downstream target genes.…”

“…This phenotype mimics hyperactive Ret signaling accompanied by increased expression of Ret downstream target genes. Interestingly, the Yap NDϪ/Ϫ phenotype is largely reduced by decreasing Ret gene dosage (48). YAP could therefore be a potential modifier of Ret in human CAKUT.…”

Interaction of the EGF Receptor and the Hippo Pathway in the Diabetic Kidney

“…Therefore, YAP and TAZ share some redundant functions, and both YAP and TAZ have been implicated in nephrogenesis [47][48][49] and in development of the urinary tract. 50 However, knockout of the YAP gene in mice leads to early embryonic lethality, 51 while knockout of TAZ induces development of renal cysts characteristic of polycystic kidney disease and lung abnormalities characteristic of emphysema. 47,48,52 In this study, we found upregulation of YAP but downregulation of TAZ expression in the diabetic kidney.…”

Integrin signalling regulates YAP and TAZ to control skin homeostasis

“…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.…”