Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme

Author:

St-Jean Guillaume1,Tsoi Mayra1,Abedini Atefeh2,Levasseur Adrien1,Rico Charlène1,Morin Martin3,Djordjevic Bojana4,Miinalainen Ilkka5,Kaarteenaho Riitta6,Paquet Marilène7,Gévry Nicolas3,Boyer Alexandre1,Vanderhyden Barbara2,Boerboom Derek1ORCID

Affiliation:

1. Département de biomédecine vétérinaire, Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, Québec, J2S 7C6, Canada

2. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada

3. Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada

4. Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, M4N 3M5, Canada

5. Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland

6. Research Unit of Internal Medicine, University of Oulu and Medical Research Center Oulu, Oulu University Hospital, 90029, Oulu, Finland

7. Département de pathologie et de microbiologie, Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, Québec, J2S 7C6, Canada

Abstract

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.

Funder

Canadian Institutes of Health Research

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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