SMAD3 directly regulates cell cycle genes to maintain arrest in granulosa cells of mouse primordial follicles

Granados-Aparici, Sofia; Hardy, Kate; Sharum, Isam; Waite, Sarah; Fenwick, Mark A.

doi:10.1038/s41598-019-42878-4

Cited by 36 publications

(38 citation statements)

References 57 publications

(68 reference statements)

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“…All of these transcripts have been reported as markers of quiescence 34 – 38 . Moreover, the key inhibitors of follicular emergence from a quiescent state Smad 2 and Smad3 39 , 40 were upregulated in NR5A2 cKO ovaries (Fig. 5 f).…”

Section: Resultsmentioning

confidence: 88%

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A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation

Meinsohn

Hughes

Estienne

et al. 2021

Sci Rep

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Liver receptor homolog-1 (NR5A2) is expressed specifically in granulosa cells of developing ovarian follicles where it regulates the late stages of follicle development and ovulation. To establish its effects earlier in the trajectory of follicular development, NR5A2 was depleted from granulosa cells of murine primordial and primary follicles. Follicle populations were enumerated in neonates at postnatal day 4 (PND4) coinciding with the end of the formation of the primordial follicle pool. The frequency of primordial follicles in PND4 conditional knockout (cKO) ovaries was greater and primary follicles were substantially fewer relative to control (CON) counterparts. Ten-day in vitro culture of PND4 ovaries recapitulated in vivo findings and indicated that CON mice developed primary follicles in the ovarian medulla to a greater extent than did cKO animals. Two subsets of primordial follicles were observed in wildtype ovaries: one that expressed NR5A2 and the second in which the transcript was absent. Neither expressed the mitotic marker. KI-67, indicating their developmental quiescence. RNA sequencing on PND4 demonstrated that loss of NR5A2 induced changes in 432 transcripts, including quiescence markers, inhibitors of follicle activation, and regulators of cellular migration and epithelial-to-mesenchymal transition. These experiments suggest that NR5A2 expression poises primordial follicles for entry into the developing pool.

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Section: Resultsmentioning

confidence: 88%

“…Their expression is associated with follicular quiescence while their loss was associated with activation 40 . SMAD3 directly maintains quiescence of granulosa cells by suppressing expression of the proto-oncogene MYC 39 , 61 . Both Smad2 and Smad3 were greater in cKO than CON ovaries, while Myc declined.…”

Section: Discussionmentioning

confidence: 99%

A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation

Meinsohn

Hughes

Estienne

et al. 2021

Sci Rep

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“…Similarly, the inhibition of type I TGFβ receptors induces an acceleration of oocyte growth and GC proliferation in cultured neonatal mouse ovaries (36). Recently, Hardy and colleagues demonstrated that nuclear SMAD2/3 expression is inversely correlated to cell proliferation in mouse ovary GCs (37), and that the loss of nuclear SMAD3, which controls the expression of cell cycle regulators such as Ccnd2 and Myc, coincides with elevated mTOR signaling to drive cell proliferation in the GCs of growing follicles (38). Comparison of differentially expressed genes between the primordial and primary stage in human GCs has identified JAK/STAT signaling as another actor mediating the primordial-to-primary follicle transition (25,39).…”

Section: Specific Tsc1 Deletion In Mouse Gcs Results In Mtorc1 Signalmentioning

confidence: 99%

Implications of Nonphysiological Ovarian Primordial Follicle Activation for Fertility Preservation

2020

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In recent years, ovarian tissue cryopreservation has rapidly developed as a successful method for preserving the fertility of girls and young women with cancer or benign conditions requiring gonadotoxic therapy, and is now becoming widely recognized as an effective alternative to oocyte and embryo freezing when not feasible. Primordial follicles are the most abundant population of follicles in the ovary, and their relatively quiescent metabolism makes them more resistant to cryoinjury. This dormant pool represents a key target for fertility preservation strategies as a resource for generating high quality oocytes. However, development of mature, competent oocytes derived from primordial follicles is challenging, particularly in larger mammals. One of the main barriers is the substantial knowledge gap regarding the regulation of the balance between dormancy and activation of primordial follicles to initiate their growing phase. In addition, experimental and clinical factors also impact dormant follicle demise, while the mechanisms involved remain largely to be elucidated. Moreover, most of our basic knowledge of these processes comes from rodent studies and should be extrapolated to humans with caution, considering the differences between species in the reproductive field. Overcoming these obstacles is essential to improving both the quantity and the quality of mature oocytes available for further fertilization, and may have valuable biological and clinical applications, especially in fertility preservation procedures. This review provides an update on current knowledge of mammalian primordial follicle activation under both physiological and non-physiological conditions, and discusses implications for fertility preservation and priorities for future research.

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“…Chronic alcohol exposure also induced the down‐regulation of Smad3 in the hippocampus in this study. Smad3, one of the Smad proteins that transduce the signals of the TGF‐β family, participates in cell cycle arrest and cell proliferation depending on cell type and circumstances . Smad3 directly induces the expression of Ccnd2 and in turn induces arrested cell cycle in granulosa cells of mouse primordial follicles, while Smad3 directly promotes Nanog, an important stem cell transcription factor, inducing self‐renewal in embryonic stem cells .…”

Section: Discussionmentioning

confidence: 99%

“…Smad3, one of the Smad proteins that transduce the signals of the TGF‐β family, participates in cell cycle arrest and cell proliferation depending on cell type and circumstances . Smad3 directly induces the expression of Ccnd2 and in turn induces arrested cell cycle in granulosa cells of mouse primordial follicles, while Smad3 directly promotes Nanog, an important stem cell transcription factor, inducing self‐renewal in embryonic stem cells . In the study by Epperly et al, Smad3 −/− mice exhibited a high population of bone marrow stromal cells at G2/M phase, implying that knockout of Smad3 − / − leads to alteration of the normal cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling in the hippocampus of adolescent rats after chronic alcohol administration

Choi

Han

Chai

et al. 2019

Basic Clin Pharma Tox

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In South Korea, the average age of onset of alcohol drinking is 13.3 years and half of adolescents drink alcohol more than once a month; 8.45% of the Korean adolescent population become future high‐risk alcohol drinkers. Chronic alcohol abuse causes physical and psychiatric health problems such as alcohol addiction, liver disease, stroke and cognitive impairments. This study aimed to investigate the effect of alcohol on gene expression and their function in the hippocampus of adolescent rats. After chronic alcohol administration in male (control, n = 6; alcohol, n = 6) Sprague‐Dawley rats for 6 weeks, we analysed up‐ or down‐regulated genes using RNA‐sequencing technology. We found 83 genes more than 1.5‐fold up‐ or down‐regulated in the alcohol‐treated group. Among them, genes (Dnai1, Cfap206 and Dnah1) associated with cilium movement were up‐regulated in the alcohol‐treated group. Mlf1, related to cell cycle arrest, was also up‐regulated in the alcohol‐treated group. On the other hand, genes (Smad3 and Plk5) involved in negative regulation of cell proliferation were down‐regulated in the hippocampus by chronic alcohol administration. In addition, expression levels of genes associated with oxidative stress (Krt8 and Car3) and migration (Vim) were changed by chronic alcohol administration. These results pave a path for a better understanding of the neuromolecular mechanisms mediated by chronic alcohol exposure in the hippocampus of adolescents and negative pathology due to chronic alcohol abuse.

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SMAD3 directly regulates cell cycle genes to maintain arrest in granulosa cells of mouse primordial follicles

Cited by 36 publications

References 57 publications

A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation

A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation

Implications of Nonphysiological Ovarian Primordial Follicle Activation for Fertility Preservation

Gene expression profiling in the hippocampus of adolescent rats after chronic alcohol administration

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