<i>Lats1</i>and<i>Lats2</i>are required for ovarian granulosa cell fate maintenance

Tsoi, Mayra; Morin, Martin; Rico, Charlène; Johnson, Randy L.; Paquet, Marilène; Gévry, Nicolas; Boerboom, Derek

doi:10.1096/fj.201900609r

Cited by 28 publications

(28 citation statements)

References 70 publications

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“…Corpora lutea were usually present, indicating that at least some follicles were able to develop fully, ovulate and luteinize. Some areas of cellular changes consistent with loss of granulosa cell differentiation were observed, as had been previously observed in the Lats1 flox/flox ; Lats2 flox/flox ; CYP19-cre model (Tsoi et al, 2019). In these areas, granulosa cells appeared to be replaced by large, round or polygonal cells with abundant, clear and slightly eosinophilic cytoplasm ( Fig.…”

Section: Loss Of Hippo Signaling Causes Müllerian Mesenchyme Cells Tsupporting

confidence: 79%

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

et al. 2019

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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.Here, we show that conditional deletion of the key Hippo kinases Lats1 and Lats2 in mouse 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 upregulation 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.

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Section: Loss Of Hippo Signaling Causes Müllerian Mesenchyme Cells Tsupporting

confidence: 79%

“…All strains were maintained on a C57BL/6J genetic background. Genotyping analyses were performed by PCR on DNA obtained from tail biopsies as previously described (Heallen et al, 2011;Tsoi et al, 2019).…”

Section: Animal Models and Fertility Trialsmentioning

confidence: 99%

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

et al. 2019

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“…In addition to the TAZ functions in the male reproductive system, TAZ has been shown to play crucial roles in oogenesis and fertilization in zebrafish and murine ovarian folliculogenesis (Dingare et al 2018;Xia et al 2019;Yi et al 2019;Bernabe et al 2020). Consistently, LATS1/2 and YAP in the Hippo pathway have been demonstrated to be essential for the proliferation of ovarian granulosa cells and maintaining normal follicle development in the female reproductive system (Plewes et al 2019;Tsoi et al 2019).…”

Section: Taz Expression Is Required For the Maintenance Of Testicularmentioning

confidence: 92%

The essential role of TAZ in normal tissue homeostasis

2021

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Transcriptional coactivator with PDZ-binding motif (TAZ) has been extensively characterized in organ development, tissue regeneration, and tumor progression. In particular, TAZ functions as a Hippo mediator that regulates organ size, tumor growth and migration. It is highly expressed in various types of human cancer, and has been reported to be associated with tumor metastasis and poor outcomes in cancer patients, suggesting that TAZ is an oncogenic regulator. Yes-associated protein (YAP) has 60% similarity in amino acid sequence to TAZ and plays redundant roles with TAZ in the regulation of cell proliferation and migration of cancer cells. Therefore, TAZ and YAP, which are encoded by paralogous genes, are referred to as TAZ/YAP and are suggested to be functionally equivalent. Despite its similarity to YAP, TAZ can be clearly distinguished from YAP based on its genetic, structural, and functional aspects. In addition, targeting superabundant TAZ can be a promising therapeutic strategy for cancer treatment; however, persistent TAZ inactivation may cause failure of tissue homeostatic control. This review focuses primarily on TAZ, not YAP, discusses its structural features and physiological functions in the regulation of tissue homeostasis, and provides new insights into the drug development targeting TAZ to control reproductive and musculoskeletal disorders.

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“…The components of Hippo signaling in granulosa cells have been reported in several mammalian species [67][68][69]. Previous reports suggest Hippo kinases large tumor suppressor kinase (LATS) 1 and 2 are required for ovarian granulosa cell fate maintenance [70] and knockout of yes-associated protein 1 (Yap1) in granulosa cells block follicle development [71]. Furthermore, disruption of the Hippo pathway has been reported to promote AKT-stimulated ovarian follicle growth [72].…”

Section: Plos Biologymentioning

confidence: 99%

Single-cell transcriptome landscape of ovarian cells during primordial follicle assembly in mice

Wang

Zhai

et al. 2020

PLoS Biol

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Primordial follicle assembly in the mouse occurs during perinatal ages and largely determines the ovarian reserve that will be available to support the reproductive life span. The development of primordial follicles is controlled by a complex network of interactions between oocytes and ovarian somatic cells that remain poorly understood. In the present research, using single-cell RNA sequencing performed over a time series on murine ovaries, coupled with several bioinformatics analyses, the complete dynamic genetic programs of germ and granulosa cells from E16.5 to postnatal day (PD) 3 were reported. Along with confirming the previously reported expression of genes by germ cells and granulosa cells, our analyses identified 5 distinct cell clusters associated with germ cells and 6 with granulosa cells. Consequently, several new genes expressed at significant levels at each investigated stage were assigned. By building single-cell pseudotemporal trajectories, 3 states and 1 branch point of fate transition for the germ cells were revealed, as well as for the granulosa cells. Moreover, Gene Ontology (GO) term enrichment enabled identification of the biological process most represented in germ cells and granulosa cells or common to both cell types at each specific stage, and the interactions of germ cells and granulosa cells basing on known and novel pathway were presented. Finally, by using single-cell regulatory network inference and clustering (SCENIC) algorithm, we were able to establish a network of regulons that can be postulated as likely candidates for sustaining germ cell-specific transcription programs throughout the period of investigation. Above all, this study provides the whole transcriptome landscape of ovarian cells and unearths new insights during primordial follicle assembly in mice.

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Lats1andLats2are required for ovarian granulosa cell fate maintenance

Cited by 28 publications

References 70 publications

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

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

The essential role of TAZ in normal tissue homeostasis

Single-cell transcriptome landscape of ovarian cells during primordial follicle assembly in mice

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