<i>Lats1</i> and <i>Lats2</i> are required for the maintenance of multipotency in the Müllerian duct mesenchyme

St-Jean, G; Tsoi, Mayra; Abedini, Atefeh; Levasseur, Adrien; Rico, Charlène; Morin, Martin; Djordjevic, Bojana; Miinalainen, Ilkka; Kaarteenaho, Riitta; Paquet, Marilène; Gévry, Nicolas; Boyer, Alexandre; Vanderhyden, Barbara C.; Boerboom, Derek

doi:10.1242/dev.180430

Cited by 11 publications

(9 citation statements)

References 65 publications

(86 reference statements)

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“…Although a recent study showed that conditional deletion of Lats1 and -2 in the Müllerian mesenchyme resulted in cell fate decision defects apparently due to increased expression of YAP and TAZ and their target genes (St-Jean et al 2019), the roles of YAP and TAZ in the physiological context of female reproductive tract development and function remained unclear. Here, we show that conditional inactivation of Yap and Taz in the oviduct results in disorderly development of the myosalpinx of the isthmus after the age of 3 weeks, suggesting their involvement in some aspect of oviduct smooth muscle cell biology.…”

Section: Yap and Taz Are Necessary For The Proper Postnatal Development Of The Myosalpinxmentioning

confidence: 99%

“…The only study of Hippo function during reproductive tract development reported thus far examined the phenotype of mice with a conditional deletion of the Hippo kinases Lats1 and Lats2 in the mesenchyme cells of the Müllerian duct. Loss of Hippo signaling in targeted cells caused them to lose their multipotency and to commit to the myofibroblast cell fate, resulting in severe developmental defects of the uterus and oviducts (St-Jean et al 2019). These changes were caused, at least in part, by markedly increased levels of YAP and TAZ protein levels, which directly drove increased transcriptional activity of Ctgf.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Yap and Taz Are Necessary For The Proper Postnatal Development Of The Myosalpinxmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Furthermore, transdifferentiation of the FLC population into myofibroblast-like cells could mechanically interfere with testis cord development. In agreement with this hypothesis, it was shown that inactivation of Lats1/2 in the Müllerian duct mesenchyme cells prior to the degradation of the Müllerian ducts in males leads to their differentiation into myofibroblasts, which in turn interfere with the development and the coiling of the adjacent epididymides [69]. Transgenic models that target Lats1/2 specifically in the Sertoli cells and the FLCs are needed to distinguish between the direct and indirect effects in each cell population.…”

Section: Discussionmentioning

confidence: 87%

“…Lineage tracing experiments would be needed to determine their origin unequivocally. Hippo signaling inactivation and YAP/TAZ transcriptional activation have also been shown to play a major roles in the transdifferentiation of cells into myofibroblasts and fibrosis in non-endocrine tissues such as the lung [ 66 ] and the heart [ 67 ] as well as in tissues derived from the intermediate mesoderm such as the kidney [ 68 ] and the Mullerian duct [ 69 ]. Among the known downstream targets of YAP/TAZ, CTGF could play an important role in the transdifferentiation of FLCs into myofibroblast-like cells.…”

Section: Discussionmentioning

confidence: 99%

Targeted Disruption of Lats1 and Lats2 in Mice Impairs Testis Development and Alters Somatic Cell Fate

Nader

Ménard

Levasseur

et al. 2022

IJMS

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Hippo signaling plays an essential role in the development of numerous tissues. Although it was previously shown that the transcriptional effectors of Hippo signaling Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) can fine-tune the regulation of sex differentiation genes in the testes, the role of Hippo signaling in testis development remains largely unknown. To further explore the role of Hippo signaling in the testes, we conditionally deleted the key Hippo kinases large tumor suppressor homolog kinases 1 and -2 (Lats1 and Lats2, two kinases that antagonize YAP and TAZ transcriptional co-regulatory activity) in the somatic cells of the testes using an Nr5a1-cre strain (Lats1flox/flox;Lats2flox/flox;Nr5a1-cre). We report here that early stages of testis somatic cell differentiation were not affected in this model but progressive testis cord dysgenesis was observed starting at gestational day e14.5. Testis cord dysgenesis was further associated with the loss of polarity of the Sertoli cells and the loss of SOX9 expression but not WT1. In parallel with testis cord dysgenesis, a loss of steroidogenic gene expression associated with the appearance of myofibroblast-like cells in the interstitial space was also observed in mutant animals. Furthermore, the loss of YAP phosphorylation, the accumulation of nuclear TAZ (and YAP) in both the Sertoli and interstitial cell populations, and an increase in their transcriptional co-regulatory activity in the testes suggest that the observed phenotype could be attributed at least in part to YAP and TAZ. Taken together, our results suggest that Hippo signaling is required to maintain proper differentiation of testis somatic cells.

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“…As reported in previous literature, deletion of either Tgfbr1 or Tbfbr2 in Amhr2+ mesenchyme caused oviductal diverticula, myometrial defects, and endometrial hyperplasia (Li et al, 2011; Ni et al, 2021). Ablations of the key Hippo kinases Lats1 and Lats2 in the Amhr2 + mesenchyme led to profound developmental defects including cystic oviducts, shortened uterine horns, and the absence of uterine glands (St-Jean et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Patterning of the female reproductive tract along antero-posterior and dorso-ventral axes is dependent on Amhr2+ mesenchyme in mice

Jia

Wilbourne

Crossen

et al. 2022

Preprint

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Morphogenesis of the female reproductive tract is regulated by the mesenchyme. However, the identity of the mesenchymal lineage that directs the patterning of the female reproductive tract has not been determined. Using in vivo genetic cell ablation, we identified Amhr2+ mesenchyme as an essential mesenchymal population in patterning the female reproductive tract. After partial ablation of Amhr2+ mesenchymal cells, the oviduct failed to develop its characteristic coiling due to decreased epithelial proliferation and tubule elongation during development. The uterus displayed a reduction in size and showed decreased cellular proliferation in both epithelial and mesenchymal compartments. More importantly, in the uterus, partial ablation of Amhr2+ mesenchyme caused abnormal lumen shape and altered the direction of its long axis from the dorsal-ventral axis to the left-right axis (i.e. perpendicular to the dorsal-ventral axis). Despite these morphological defects, epithelia underwent normal differentiation into secretory and ciliated cells in the oviduct and glandular epithelial cells in the uterus. These results demonstrated that Amhr2+ mesenchyme can direct female reproductive tract morphogenesis by regulating epithelial proliferation and lumen shape without affecting the differentiation of epithelial cell types.

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

Cited by 11 publications

References 65 publications

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

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

Targeted Disruption of Lats1 and Lats2 in Mice Impairs Testis Development and Alters Somatic Cell Fate

Patterning of the female reproductive tract along antero-posterior and dorso-ventral axes is dependent on Amhr2+ mesenchyme in mice

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