Defective Gonadotropin-Dependent Ovarian Folliculogenesis and Granulosa Cell Gene Expression in Inhibin-Deficient Mice

Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Endocrinology (Impact Factor: 4.5). 10/2010; 151(10):4994-5006. DOI: 10.1210/en.2010-0428
Source: PubMed


Inhibin-α knockout (Inha-/-) female mice develop sex cord-stromal ovarian cancer with complete penetrance and previous studies demonstrate that the pituitary gonadotropins (FSH and LH) are influential modifiers of granulosa cell tumor development and progression in inhibin-deficient females. Recent studies have demonstrated that Inha-/- ovarian follicles develop precociously to the early antral stage in prepubertal mice without any increase in serum FSH. These studies suggest that in the absence of inhibins, granulosa cells differentiate abnormally and thus at sexual maturity may undergo an abnormal response to gonadotropin signaling contributing to tumor development. To test this hypothesis, we stimulated immature wild-type and Inha-/- female mice with gonadotropin analogs prior to tumor formation and subsequently examined gonadotropin-induced ovarian follicle development as well as preovulatory and human chorionic gonadotropin-induced gene expression changes in granulosa cells. We find that at 3 wk of age, inhibin-deficient ovaries do not show further antral development or undergo cumulus expansion. In addition, there are widespread alterations in the transcriptome of gonadotropin-treated Inha-/- granulosa cells, with significant changes in genes involved in extracellular matrix and cell-cell communication. These data indicate the gonadotropins initiate an improper program of cell differentiation prior to tumor formation in the absence of inhibins.

Download full-text


Available from: Stephanie Pangas, Apr 17, 2014
  • Source
    • "Genes belonging to TGFB superfamily are important regulators; they are called also “checkpoints of oocyte maturation potential" [23]. INHA and INHB are members of TGFB superfamily and it is suggested that they regulate important stages of oocyte maturation in vivo and in vitro [24–26]. However, the influence of several factors, for example, the follicular size and/or in vitro cultivation, on INHA and INHB mRNA expression profile or encoded proteins distribution within the porcine oocytes, is still not entirely known. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cumulus-oocyte-complexes (COCs) were collected from small (<3 mm), medium (3-5 mm), and large (>5 mm) porcine follicles, and the INHA and INHB expression and cellular localization were studied. Developmentally competent (BCB+) COCs were cultured for 44 h. Samples of mRNA were isolated before and after in vitro maturation (IVM) from oocytes collected from follicles of different size for RQ-PCR assay. The INHA and INHB protein distribution within the oocytes was observed by confocal microscopy. INHA mRNA expression was increased in oocytes from large compared to medium and small follicles before IVM (P < 0.001), and to oocytes of small follicles after IVM (P < 0.001). The INHB expression was not different before IVM, but the IHNB mRNA level was gradually higher in oocytes from large follicles after IVM (P < 0.01). INHA was not differently expressed before IVM; however, in large follicle oocytes the protein was distributed in the peripheral area of the cytoplasm; in oocytes from small follicles it was in the entire cytoplasm. After IVM, INHA was strongly expressed in oocytes from small follicles and distributed particularly in the zona pellucida (ZP). Similarly and both before and after IVM, INHB protein was highly expressed in small follicle oocytes and within the cytoplasm. In summary, INHs can be recognized as a marker of porcine oocyte quality.
    Full-text · Article · Nov 2012 · BioMed Research International
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite rapid progress in characterizing transcription factor-driven reprogramming of somatic cells to an induced pluripotent stem cell (iPSC) state, many mechanistic questions still remain. To gain insight into the earliest events in the reprogramming process, we systematically analyzed the transcriptional and epigenetic changes that occur during early factor induction after discrete numbers of divisions. We observed rapid, genome-wide changes in the euchromatic histone modification, H3K4me2, at more than a thousand loci including large subsets of pluripotency-related or developmentally regulated gene promoters and enhancers. In contrast, patterns of the repressive H3K27me3 modification remained largely unchanged except for focused depletion specifically at positions where H3K4 methylation is gained. These chromatin regulatory events precede transcriptional changes within the corresponding loci. Our data provide evidence for an early, organized, and population-wide epigenetic response to ectopic reprogramming factors that clarify the temporal order through which somatic identity is reset during reprogramming.
    Full-text · Article · Jan 2011 · Cell stem cell
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ovarian cancer may be the most frequently lethal gynaecological malignancy but the heterogeneous nature of the disease and the advanced stage at which it is usually diagnosed, have contributed to the paucity of information relating to its aetiology and pathogenesis. Members of the TGF-β superfamily, estrogen and NFκB have all been implicated in the development and progression of cancers from a wide range of tissues. In the ovary, TGF-β superfamily members and estrogen play key roles in maintaining normal function. To date, little is known about the capacity of NFκB to influence normal ovarian function except that it is ubiquitously expressed. In this review we will highlight the roles that inhibin/activin, estrogen and NFκB, have been attributed within carcinogenesis and examine the potential for crosstalk between these pathways in ovarian cancer pathogenesis.
    No preview · Article · Aug 2011 · Molecular and Cellular Endocrinology
Show more