Synaptosomal-Associated Protein 25 Gene Expression Is Hormonally Regulated during Ovulation and Is Involved in Cytokine/Chemokine Exocytosis from Granulosa Cells

Shimada, M.; Yanai, Yoshiari; Okazaki, Tetsuji; Yamashita, Yugo; Sriraman, Venkataraman; Wilson, Michael C.; Richards, JoAnne S.

doi:10.1210/me.2007-0042

Cited by 66 publications

(76 citation statements)

References 61 publications

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“…It is postulated that PR, a ligand-inducible transcription factor, controls ovulation by regulating the expression of a unique network of downstream genes. Consistent with this hypothesis, Richards and coworkers identified three novel genes, a disintegrin and metalloprotease with thromboxan motif 1 (ADAMTS-1) (29), cyclic GMP-dependent protein kinase II (cGKII) (34), and synaptosome-associated protein 25 (Snap25) (32), as potential mediators of PR function in the ovary. Our laboratory has recently reported that endothelin-2 (ET-2), which is induced in the preovulatory follicles in a PR-dependent manner, is a critical regulator of follicular rupture (25).…”

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confidence: 85%

Peroxisome Proliferator-Activated Receptor γ Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice

Kim

Sato²,

et al. 2008

Molecular and Cellular Biology

109

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The progesterone receptor (PR) plays a critical role during ovulation. Mice lacking the PR gene are anovulatory due to a failure in the rupture of the preovulatory follicles. The pathways that operate downstream of PR to control ovulation are poorly understood. Using gene expression profiling, we identified peroxisome proliferator-activated receptor ␥ (PPAR␥) as a target of regulation by PR in the granulosa cells of the preovulatory follicles during the ovulatory process. To investigate the function of PPAR␥ during ovulation, we created a conditional knockout mouse in which this gene was deleted via Cre-Lox-mediated excision in granulosa cells. When these mutant mice were subjected to gonadotropin-induced superovulation, the preovulatory follicles failed to rupture and the number of eggs released from the mutant ovaries declined drastically. Gene expression analysis identified endothelin-2, interleukin-6, and cyclic GMP-dependent protein kinase II as novel targets of regulation by PPAR␥ in the ovary. Our studies also suggested that cycloxygenase 2-derived metabolites of long-chain fatty acids function as endogenous activating ligands of PPAR␥ in the preovulatory follicles. Collectively, these studies revealed that PPAR␥ is a key mediator of the biological actions of PR in the granulosa cells and activation of its downstream pathways critically controls ovulation.Ovulation is a key female reproductive event which involves the release of a fertilizable oocyte from a mature ovarian follicle (28). In mammals, it is a highly coordinated process regulated by endocrine/paracrine factors produced by the hypothalamic-pituitary-ovarian axis. During each reproductive cycle in the rodent, follicle-stimulating hormone, synthesized by the pituitary gonadotrophs, promotes the growth and development of a selected pool of preantral follicles to the preovulatory stage. The action of follicle-stimulating hormone is followed by a timely surge of another pituitary gonadotropin, luteinizing hormone (LH), which triggers ovulation. The preovulatory surge of LH sets in motion a complex cascade of gene expression events in the follicular cells that culminates in the rupture of the preovulatory follicle (27). Genetic analyses of the mouse established that the genes encoding progesterone (P) receptor (PR) (26), cyclooxygenase 2 (COX-2) (7, 21), and CCAAT/enhancer binding protein ␤ (36), which are induced in the granulosa cells following LH action, play obligatory roles during ovulation.The steroid hormone P, acting via its cellular receptor, plays an essential role during ovulation (22,23). Previous studies have shown that the PR is rapidly induced in the mural granulosa cells of the preovulatory follicles following the LH surge (26, 29). Development of a mouse model lacking PR by Lydon et al. revealed an indispensable role for this hormone receptor during ovulation (23). In PR-null mice, follicular development to the antral stage proceeds unaffected. These mutant mice, however, fail to ovulate due to a block in follicular rupture, even wh...

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mentioning

confidence: 85%

Peroxisome Proliferator-Activated Receptor γ Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice

Kim

Sato²,

et al. 2008

Molecular and Cellular Biology

109

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“…These proteins include NSF, ␣ -SNAP, SNARE, SNAP23, syntaxin-5, and VAMP4. Steroidogenic cells express high levels of some members of the SNARE protein family, such as Syntaxin-17, SNAP23, and SNAP25; these are hormonally regulated in ovarian granulosa cells (154)(155)(156)(157)(158). SNARE additional introns present in the MLN64-START domain genomic sequence are also conserved.…”

Section: Transport Of Cholesterol To Mitochondria: Cholesterol-bindinmentioning

confidence: 99%

Early steps in steroidogenesis: intracellular cholesterol trafficking

Miller

Bose

2011

Journal of Lipid Research

457

398

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“…Because the induction of IL-6 is regulated not only by AREG (115) but also by progesterone receptor (PGR) (115,119) and C/EBPβ, both of which are essential for ovulation, it is tempting to speculate that IL-6 may mediate some key process downstream of PGR and C/EBPβ in granulosa cells or cumulus cells. Moreover, the expression of synaptosomal-associated protein 25 (SNAP25), an important component controlling neuronal-like secretion of cytokines from granulosa cells, is also regulated by PGR (120). Thus, the importance of locally produced and secreted ovarian cell-derived cytokines during ovulation needs to be analyzed further, and these cytokines may affect several ovulation-related processes including follicle rupture, COC transport, and fertilization (117).…”

Section: New Insights Into Factors Controlling Ovulation and Luteinizmentioning

confidence: 99%

The ovary: basic biology and clinical implications

Richards

Pangas²

2010

J. Clin. Invest.

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424

276

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The classical view of ovarian follicle development is that it is regulated by the hypothalamic-pituitary-ovarian axis, in which gonadotropin-releasing hormone (GnRH) controls the release of the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and that ovarian steroids exert both negative and positive regulatory effects on GnRH secretion. More recent studies in mice and humans indicate that many other intra-ovarian signaling cascades affect follicular development and gonadotropin action in a stage-and context-specific manner. As we discuss here, mutant mouse models and clinical evidence indicate that some of the most powerful intraovarian regulators of follicular development include the TGF-β/SMAD, WNT/FZD/β-catenin, and RAS/ERK1/2 signaling pathways and the FOXO/FOXL2 transcription factors. IntroductionThe ovary is a highly organized composite of germ cells (oocytes or eggs) and somatic cells (granulosa cells, thecal cells, and stromal cells) whose interactions dictate formation of oocyte-containing follicles, development of both oocytes and somatic cells as follicles, ovulation, and formation of the corpus luteum (the endocrine structure that forms from the ovarian follicle after ovulation and is required for establishing and maintaining pregnancy) (Figure 1). Many events in the adult ovary are controlled by two hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), secreted from the anterior pituitary gland under the control of pulses of gonadotropin-releasing hormone (GnRH) from the hypothalamus (Figure 1). Low-frequency GnRH pulses stimulate a slight increase in FSH levels early in a woman's menstrual cycle, enhancing follicle growth, while high-frequency GnRH pulses lead to a sharp rise in levels of LH just before mid-cycle (an event known as the "LH surge"), triggering ovulation and formation of the corpus luteum (Figure 1). The ovary also has a key role in these processes, ensuring the timely release of fertilizable oocytes and the maintenance of luteal cell function, a necessity for pregnancy, by directing feedback mechanisms to the hypothalamus and pituitary. For example, estrogen produced by the cells of the developing follicle both inhibits GnRH production in the hypothalamus and elicits elevated GnRH pulses, which trigger the mid-cycle LH surge that initiates ovulation. Thus, fertility depends on highly orchestrated endocrine events involving multiple organ systems.Disruption of this finely controlled network can lead to many clinical syndromes including premature ovarian failure (POF), polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome, ovulation defects, poor oocyte quality, and cancer. The goal of this Review is to cover some of the advances in our understanding of the basic biology of the mammalian ovary that may shed light on specific ovarian dysfunctions that lead to infertility. We primarily focus on recent developments using mouse genetic models to study follicle growth and ovarian function because of the inherent di...

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Synaptosomal-Associated Protein 25 Gene Expression Is Hormonally Regulated during Ovulation and Is Involved in Cytokine/Chemokine Exocytosis from Granulosa Cells

Cited by 66 publications

References 61 publications

Peroxisome Proliferator-Activated Receptor γ Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice

Peroxisome Proliferator-Activated Receptor γ Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice

Early steps in steroidogenesis: intracellular cholesterol trafficking

The ovary: basic biology and clinical implications

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