Hormonal Signal Amplification Mediates Environmental Conditions during Development and Controls an Irreversible Commitment to Adulthood

Many animals can choose between different developmental fates to maximize fitness. Despite the complexity of environmental cues and life history, different developmental fates are executed in a robust fashion. The nematode Caenorhabditis elegans serves as a powerful model to examine this phenomenon because it can adopt one of two developmental fates (adulthood or diapause) depending on environmental conditions. The steroid hormone dafachronic acid (DA) directs development to adulthood by regulating the transcriptional activity of the nuclear hormone receptor DAF-12. The known role of DA suggests that it may be the molecular mediator of environmental condition effects on the developmental fate decision, although the mechanism is yet unknown. We used a combination of physiological and molecular biology techniques to demonstrate that commitment to reproductive adult development occurs when DA levels, produced in the neuroendocrine XXX cells, exceed a threshold. Furthermore, imaging and cell ablation experiments demonstrate that the XXX cells act as a source of DA, which, upon commitment to adult development, is amplified and propagated in the epidermis in a DAF-12 dependent manner. This positive feedback loop increases DA levels and drives adult programs in the gonad and epidermis, thus conferring the irreversibility of the decision. We show that the positive feedback loop canalizes development by ensuring that sufficient amounts of DA are dispersed throughout the body and serves as a robust fate-locking mechanism to enforce an organism-wide binary decision, despite noisy and complex environmental cues. These mechanisms are not only relevant to C. elegans but may be extended to other hormonal-based decision-making mechanisms in insects and mammals

Aromatase expression is increased in BRCA1 mutation carriers

<p>Abstract</p> <p>Background</p> <p>Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of <it>BRCA1 </it>gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression <it>in vitro</it>. Our objective was to characterise aromatase gene <it>(CYP19A1) </it>and its promoter expression in breast adipose and ovarian tissue in <it>BRCA1 </it>mutation carriers and unaffected controls.</p> <p>Methods</p> <p>We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women.</p> <p>Results</p> <p>We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of <it>BRCA1 </it>mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts.</p> <p>Conclusion</p> <p>Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in <it>BRCA1 </it>mutation carriers.</p

MicroRNA Expression and Regulation in Human Ovarian Carcinoma Cells by Luteinizing Hormone

MicroRNAs have been widely-studied with regard to their aberrant expression and high correlation with tumorigenesis and progression in various solid tumors. With the major goal of assessing gonadotropin (luteinizing hormone, LH) contributions to LH receptor (LHR)-positive ovarian cancer cells, we have conducted a genome-wide transcriptomic analysis on human epithelial ovarian cancer cells to identify the microRNA-associated cellular response to LH-mediated activation of LHR.Human ovarian cancer cells (SKOV3) were chosen as negative control (LHR-) and stably transfected to express functional LHR (LHR+), followed by incubation with LH (0-20 h). At different times of LH-mediated activation of LHR the cancer cells were analyzed by a high-density Ovarian Cancer Disease-Specific-Array (DSA, ALMAC™), which profiled ∼ 100,000 transcripts with ∼ 400 non-coding microRNAs.In total, 65 microRNAs were identified to exhibit differential expression in either LHR expressing SKOV3 cells or LH-treated cells, a few of which have been found in the genomic fragile regions that are associated with abnormal deletion or amplification in cancer, such as miR-21, miR-101-1, miR-210 and miR-301a. By incorporating the dramatic expression changes observed in mRNAs, strong microRNA/mRNA regulatory pairs were predicted through statistical analyses coupled with collective computational prediction. The role of each microRNA was then determined through a functional analysis based on the highly-confident microRNA/mRNA pairs.The overall impact on the transcriptome-level expression indicates that LH may regulate apoptosis and cell growth of LHR+ SKOV3 cells, particularly by reducing cancer cell proliferation, with some microRNAs involved in regulatory roles

Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence

background: Polycystic ovary syndrome (PCOS) is a common metabolic dysfunction and heterogeneous endocrine disorder in women of reproductive age. Although patients with PCOS are typically characterized by increased numbers of oocytes retrieved during IVF, they are often of poor quality, leading to lower fertilization, cleavage and implantation rates, and a higher miscarriage rate. methods: For this review, we searched the database MEDLINE (1950 to January 2010) and Google for all full texts and/or abstract articles published in English with content related to oocyte maturation and embryo developmental competence. results: The search showed that alteration of many factors may directly or indirectly impair the competence of maturating oocytes through endocrine and local paracrine/autocrine actions, resulting in a lower pregnancy rate in patients with PCOS. The extra-ovarian factors identified included gonadotrophins, hyperandrogenemia and hyperinsulinemia, although intra-ovarian factors included members of the epidermal, fibroblast, insulin-like and neurotrophin families of growth factors, as well as the cytokines. conclusions: Any abnormality in the extra- and/or intra-ovarian factors may negatively affect the granulosa cell-oocyte interaction, oocyte maturation and potential embryonic developmental competence, contributing to unsuccessful outcomes for patients with PCOS who are undergoing assisted reproduction.Obstetrics &amp; GynecologyReproductive BiologySCI(E)PubMed49REVIEW117-331