YAP and TAZ are required for the postnatal development and the maintenance of the structural integrity of the oviduct

Abstract

The development of the Müllerian ducts into the female reproductive tract requires the coordination of multiple signaling pathways that regulate proliferation, apoptosis and differentiation. The Hippo pathway has been reported to interact with several pathways with established roles in Müllerian duct development; yet, its potential roles in reproductive tract development and function remain mostly uncharacterized. The objective of this study was therefore to characterize the roles of the Hippo transcriptional coactivators YAP and TAZ in the female reproductive tract using transgenic mouse models. This report shows that the concomitant conditional inactivation of Yap and Taz in the mouse Müllerian duct mesenchyme results in postnatal developmental defects of the oviduct. Most notably, discontinuities in the myosalpinx layer lead to the progressive formation of cystic dilations of the isthmus. These defects prevented embryo transport and subsequent implantation in older animals, causing infertility. The loss of YAP/TAZ did not appear to affect other biological processes known to be required for the maintenance of oviductal wall integrity, such as TGF-β/SMAD and Notch signaling and the biogenesis of miRNA, suggesting that the Hippo pathway acts independently of these processes to direct oviduct development. Taken together, these results suggest redundant and essential roles for YAP and TAZ in the postnatal development of the oviduct and the maintenance of its structural integrity.

Context-dependent roles of YAP/TAZ in stem cell fates and cancer

“…During the earliest stages of embryogenesis, loss of either gene individually does not cause a pre-implantation defect; however, dual knockout (KO) Yap1 −/− ;Wwtr1 −/− embryos die before the 32 cell stage, implying that they are essential but redundant for morula formation [30]. While more sophisticated conditional KOs have shown that Yap1 plays critical roles in the cranial neural crest, female reproductive tract, and heart valves, these phenotypes tended to be late or post-natal, and it would be fruitful to apply conditional KO in the early embryo or placenta to revisit the null phenotypes [31][32][33].…”

“…As paralogs with high (~ 50%) sequence identity, these two proteins possess both redundant (i.e., they can genetically compensate for one another) and non-redundant roles [2]. They have a similar target gene profile, and they are redundant in the oviduct, heart, urinary tract, and other organs [31,[103][104][105]. However, they have numerous context-specific differences and fulfill distinct roles during embryogenesis and cell fate specification.…”

“…Despite the existence of these models, they have not been used to elucidate embryogenesis-related functions of YAP in greater depth. Recently, hESCs have been used to generate a trophoblastic spheroid that has been proposed as a blastocyst surrogate; YAP expression is more intense and nuclear in these spheroids, and inhibition of YAP leads to defects in attachment and outgrowth [ 101 ]. This is promising, but follow-up studies are needed.…”

VGLL3 expression is associated with macrophage infiltration and predicts poor prognosis in epithelial ovarian cancer

“…The hippo pathway is a critical regulator of morphogenesis, organ size determination, and tumourigenesis in many tissues, including the reproductive system [10][11][12]. Formation of the YAP/TAZ-TEADs complex serves as the key mechanism that stimulates the expression of target genes (e.g., connective tissue growth factor and cysteine-rich angiogenic inducer 61) that are essential for cell proliferation and survival [13].…”

Microvascularization and Expression of Fibroblast Growth Factor and Vascular Endothelial Growth Factor and Their Receptors in the Mare Oviduct

“…This is a very complex process. In the reproductive system, including the oviduct, angiogenesis is modulated by angiogenic/growth factors [7,8,10], anti-angiogenic factors [11][12][13], reproductive hormones [14,15], eicosanoids [9,16], nitric oxide [16,17], tumor necrosis factor α (TNFα) [18], oxygen (O 2 ) content [19,20], and other factors [21][22][23]. Among a plethora of angiogenic/growth factors are vascular endothelial growth factor (VEGF) and its receptors 1 (VEGFR1) and 2 (VEGFR2, also known as kinase insert domain receptor-KDR) and fibroblast growth factor 1 and 2 (FGF1 and FGF2) and their receptors FGFR1 and FGFR2 [24][25][26][27][28].…”