WNT signaling plays essential roles in the development and function of the female reproductive tract. Although crosstalk with the Hippo pathway is a key regulator of WNT signaling, whether Hippo itself plays a role in female reproductive biology remains largely unknown. In this report, we show that conditional deletion of the key Hippo kinases Lats1 and Lats2 in Müllerian duct mesenchyme cells caused them to adopt the myofibroblast cell fate, resulting in profound reproductive tract developmental defects and sterility. Myofibroblast differentiation was attributed to increased YAP and TAZ expression (but not to altered WNT signaling), leading to the direct transcriptional up-regulation of Ctgf and the activation of the myofibroblast genetic program. Müllerian duct mesenchyme cells also became myofibroblasts in male mutant embryos, which impeded the development of the male reproductive tract and resulted in cryptorchidism. The inactivation of Lats1/2 in differentiated uterine stromal cells in vitro did not compromise their ability to decidualize, suggesting that Hippo is dispensable during implantation. We conclude that Hippo signaling is required to suppress the myofibroblast genetic program and maintain multipotency in Müllerian mesenchyme cells.
Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme
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Guillaume St-Jean, Mayra Tsoi, Atefeh Abedini, Adrien Levasseur, Charlène Rico, Martin Morin, Bojana Djordjevic, Ilkka Miinalainen, Riitta Kaarteenaho, Marilène Paquet, Nicolas Gévry, Alexandre Boyer, Barbara Vanderhyden, Derek Boerboom; Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme. Development 2019; dev.180430. doi: https://doi.org/10.1242/dev.180430
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