ESR2 regulates granulosa cell genes essential for follicle maturation and ovulation

Khristi, Vincentaben; Chakravarthi, V. Praveen; Singh, Prabhakar; Ghosh, Subhra; Pramanik, Archit; Ratri, Anamika; Borosha, Shaon; Roby, Katherine F.; Wolfe, Michael W.; Rumi, M.A. Karim

doi:10.1016/j.mce.2018.03.012

Cited by 68 publications

(73 citation statements)

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“…We also detected a dramatic upregulation of Kiss1 gene expression in GCs following the administration of hCG to PMSG primed rats (Chakravarthi et al, 2020;Chakravarthi et al, 2018;Khristi et al, 2018). The expression pattern of Kiss1 and Kiss1r (Chakravarthi et al, 2018) suggest that GC-derived KISS1 may act on the KISS1R in oocytes to regulate oocyte maturation (Fig.…”

Section: Discussionmentioning

confidence: 62%

“…We have studied the role of ovarian derived KISS1 using an Erβ null mutant rat model that fails to induce Kiss1 gene expression in GCs in response to gonadotropins (Chakravarthi et al, 2020;Chakravarthi et al, 2018;Khristi et al, 2018) and suffer from defective oocyte maturation.…”

Section: Discussionmentioning

confidence: 99%

“…However, treatment with exogenous gonadotropins fails to induce ovulation, suggesting a primary ovarian defect due to the loss of ERβ (Rumi et al, 2017). To identify the ERβ-regulated genes that may affect ovarian follicle development, oocyte maturation, and ovulation, we performed RNAsequencing analyses of gonadotropin stimulated granulosa cells (GCs) and oocytes (Chakravarthi et al, 2020;Chakravarthi et al, 2019;Khristi et al, 2018). We identified Kiss1 to be one of the most-differentially expressed gene in Erβ null GCs (Chakravarthi et al, 2020;Khristi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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ERβ regulated ovarian kisspeptin plays an important role in oocyte maturation

Chakravarthi

Ghosh

Roby

et al. 2020

Preprint

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Kisspeptin (KISS1) signaling in the hypothalamic-pituitary (H-P) axis plays essential role in regulating gonadotropin secretion. KISS1 and KISS1 receptor (KISS1R) are also expressed in the ovary; however, the role of intraovarian KISS1 signaling remains largely unclear. Granulosa cell (GC)-specific expression of KISS1, and oocyte-specific expression of KISS1R indicate that GC-derived KISS1 may act on oocytes. Expression of KISS1 in GCs is induced by gonadotropins but it is absent in estrogen receptor β knockout (Erβnull) rats. We also observed that gonadotropin stimulation failed to induce maturation of Erβnull oocytes. Interestingly, KISS1 treatment of cumulus oocyte complexes (COCs) isolated from antral follicles promotes in vitro maturation of oocytes. Treatment of oocytes with KISS1 induced intracellular Ca2+ release, and increased activation of MAP kinase ERK1/2. KISS1 treatment also induced the expression of oocyte genes that are crucial for differentiation of GCs, and maturation of oocytes. Our findings suggest that ovarian KISS1-signaling plays an important role in gonadotropin induced follicle development and oocyte maturation.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ERβ regulated ovarian kisspeptin plays an important role in oocyte maturation

Chakravarthi

Ghosh

Roby

et al. 2020

Preprint

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“…We observed that Erβ null ovarian follicles fail to develop beyond the antral stage. Previous studies have focused on the attenuated gonadotropin surge and defective expression of GC genes involved in the preovulatory process (Khristi et al, 2018;Rumi et al, 2017). However, ERβ is the predominant estrogen receptor expressed in the ovary since the embryonic stage (Byers et al, 1997b;Couse et al, 2004a;Pelletier and El-Alfy, 2000a;Slomczynska et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Chakravarthi

Borosha

Ghosh

et al. 2020

Preprint

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Follicle development beyond the preantral stage is dependent on gonadotropins. FSH signaling is crucial for the advancement of preantral follicles to the antral stage, and LH signaling is essential for further maturation of preovulatory follicles. Estrogen is intricately tied to gonadotropin signaling during the advanced stages of folliculogenesis. We observed that Erβnull ovarian follicles fail to develop beyond the antral stage, even after exogenous gonadotropin stimulation. As ERβ is primarily expressed in the granulosa cells (GCs), we explored the gonadotropin-regulated GC genes that induce maturation of antral follicles. Synchronized follicle development was induced by administration of exogenous gonadotropins to wildtype 4-wk-old female rats. The GC transcriptome was analyzed via RNA-sequencing before and after gonadotropin stimulation. An Erβnull mutant model that fails to show follicle maturation was also included in order to identify the ERβ-regulated genes involved at this step. We observed that specific groups of genes were differentially expressed in response to PMSG or hCG administration in wildtype rats. While some of the PMSG or hCG-induced genes showed a similar expression pattern in Erβnull GCs, a subset of PMSG- or hCG-induced genes showed a differential expression in Erβnull GCs. These latter ERβ-regulated genes included previously known FSH or LH target genes including Lhcgr, Cyp11a1, Cyp19a1, Pgr, Runx2, Egfr, Kiss1, and Ptgs2, which are involved in follicle development, oocyte maturation, and ovulation. We also identified novel ERβ-regulated genes including Jaml, Galnt6, Znf750, Dusp9, Wnt16, and Mageb16 that failed to respond to gonadotropin stimulation in Erβnull GCs. Our findings indicate that the gonadotropin-induced spatiotemporal pattern of gene expression is essential for ovarian follicle maturation beyond the antral stage. However, expression of a subset of those gonadotropin-induced genes is dependent on transcriptional regulation by ERβ.

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“…Oocyte development is fulfilled in a follicle unit, which consists of somatic follicle cells that encase the oocyte. Proper proliferation and differentiation of somatic follicle cells are essential for oocyte development and, ultimately, for release of the functional oocytes through ovulation (Khristi et al, 2018;Robker et al, 2018); however, the molecular mechanisms regulating somatic follicle cell differentiation and follicle maturation in the final preovulatory stages are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of homeodomain protein Cut is essential for follicle maturation and ovulation

Knapp

Sun

2019

Development

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Proper development and maturation of a follicle is essential for successful ovulation and reproduction; however, the molecular mechanisms for follicle maturation, particularly for somatic follicle cell differentiation, are poorly understood. During Drosophila oogenesis, the somatic follicle cells encasing oocytes undergo two distinct well-established transitions: the mitotic to endocycle switch at stage 6/7 and the endocycle to gene amplification switch at stage10A/10B. Here, we identify a novel third follicle cell transition that occurs in the final stages of oogenesis (stage 13/14). This late follicle cell transition is characterized by upregulation of the transcription factor Hindsight (Hnt), and downregulation of the homeodomain transcription factor Cut and the zinc-finger transcription factor Tramtrack-69 (Ttk69). We demonstrate that inducing expression of Cut in stage 14 follicle cells is sufficient to inhibit follicle rupture and ovulation through its negative regulation of Hnt and promotion of Ttk69 expression. Our work illustrates the importance of the stage13/14 transition for follicle maturation and demonstrates the complex regulation required for somatic follicle cells to differentiate into a state primed for follicle rupture and ovulation.

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ESR2 regulates granulosa cell genes essential for follicle maturation and ovulation

Cited by 68 publications

References 54 publications

ERβ regulated ovarian kisspeptin plays an important role in oocyte maturation

ERβ regulated ovarian kisspeptin plays an important role in oocyte maturation

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Downregulation of homeodomain protein Cut is essential for follicle maturation and ovulation

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