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Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice.

ABSTRACT: The microRNA (miRNA) processing enzyme Dicer1 is required for zygotic and embryonic development, but the early embryonic lethality of Dicer1 null alleles in mice has limited our ability to address the role of Dicer1 in normal mouse growth and development. To address this question, we used a mouse mutant with a hypomorphic Dicer1 allele (Dicer(d/d)) and found that Dicer1 deficiency resulted in female infertility. This defect in female Dicer(d/d) mice was caused by corpus luteum (CL) insufficiency and resulted, at least in part, from the impaired growth of new capillary vessels in the ovary. We found that the impaired CL angiogenesis in Dicer(d/d) mice was associated with a lack of miR17-5p and let7b, 2 miRNAs that participate in angiogenesis by regulating the expression of the antiangiogenic factor tissue inhibitor of metalloproteinase 1. Furthermore, injection of miR17-5p and let7b into the ovaries of Dicer(d/d) mice partially normalized tissue inhibitor of metalloproteinase 1 expression and CL angiogenesis. Our data indicate that the development and function of the ovarian CL is a physiological process that appears to be regulated by miRNAs and requires Dicer1 function.

SUBMITTER: Otsuka M

PROVIDER: S-EPMC2289794 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice.

Otsuka Motoyuki M Zheng Min M Hayashi Masaaki M Lee Jing-Dwan JD Yoshino Osamu O Lin Shengcai S Han Jiahuai J

The Journal of clinical investigation 20080501 5

The microRNA (miRNA) processing enzyme Dicer1 is required for zygotic and embryonic development, but the early embryonic lethality of Dicer1 null alleles in mice has limited our ability to address the role of Dicer1 in normal mouse growth and development. To address this question, we used a mouse mutant with a hypomorphic Dicer1 allele (Dicer(d/d)) and found that Dicer1 deficiency resulted in female infertility. This defect in female Dicer(d/d) mice was caused by corpus luteum (CL) insufficiency ...[more]

PMID: 18398510

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Project description:The formation, function, and subsequent regression of the ovarian corpus luteum (CL) are dynamic processes that enable ovary cyclical activity. Studies in whole ovary tissue have found microRNAs (miRNAs) to by critical for ovary function. However, relatively little is known about the role of miRNAs in the bovine CL. Utilizing small RNA next-generation sequencing we profiled miRNA transcriptome in bovine CL during the entire physiological estrous cycle, by sampling the CL on days: d 1-2, d 3-4, and d 5-7 (early CL, eCL), d 8-12 (mid CL, mCL), d 13-16 (late CL, lCL), and d > 18 (regressed CL, rCL). We characterized patterns of miRNAs abundance and identified 42 miRNAs that were consistent significantly different expressed (DE) in the eCL relative to their expression at each of the analyzed stages (mCL, lCL, and rCL). Out of these, bta-miR-210-3p, -2898, -96, -7-5p, -183-5p, -182, and -202 showed drastic up-regulation with a fold-change of ?2.0 and adjusted P < 0.01 in the eCL, while bta-miR-146a was downregulated at lCL and rCL vs. the eCL. Another 24, 11, and 21 miRNAs were significantly DE only between individual comparisons, eCL vs. the mCL, lCL, and rCL, respectively. Irrespective of cycle stage two miRNAs, bta-miR-21-5p and bta-miR-143 were identified as the most abundant miRNAs species and show opposing expression abundance. Whilst bta-miR-21-5p peaked in number of reads in the eCL and was significantly downregulated in the mCL and lCL, bta-miR-143 reached its peak in the rCL and is significantly downregulated in the eCL. MiRNAs with significant DE in at least one cycle stage (CL class) were further grouped into eight distinct clusters by the self-organizing tree algorithm (SOTA). Half of the clusters contain miRNAs with low-expression, whilst the other half contain miRNAs with high-expression levels during eCL. Prediction analysis for significantly DE miRNAs resulted in target genes involved with CL formation, functionalization and CL regression. This study is the most comprehensive profiling of miRNA transcriptome in bovine CL covering the entire estrous cycle and provides a compact database for further functional validation and biomarker identification relevant for CL viability and fertility.

Project description:UnlabelledObesity and malnutrition are associated with decreased fecundity in women. Impaired reproductive capacity in obese women is often attributed to anovulation. However, obese women with ovulatory cycles also have reduced fertility, but the etiology of their impaired reproduction is only partially understood. Accumulating evidence suggests that obesity directly impairs oocyte and embryo quality as well as endometrial receptivity. In obese women, urinary progesterone metabolite excretion is decreased, but in excess of what can be explained by suppressed gonadotropin secretion, suggesting that apart from its central effect obesity may directly affect progesterone (P4) production. These observations have led to the novel hypothesis that obesity directly affects corpus luteum (CL) function. Similarly, we hypothesize that weight loss may contribute to luteal dysfunction. Here, we propose a non-human primate model, the vervet monkey, to examine the effect of weight gain and loss on menstrual cycle parameters and CL gene expression. In this model, weight gain and loss did not significantly alter menstrual cyclicity; however, both induced alterations in the CL transcriptome. In the weight gain monkey, we observed that impaired mid-luteal P4 secretion was associated with downregulation of steroidogenic pathways in CL. Collectively, these preliminary findings support our hypothesis that weight gain and loss may contribute to CL dysfunction. The vervet model described and preliminary observations provide a basis for a larger study to address this important question. Understanding the mechanisms by which weight gain and loss contribute to reproductive dysfunction can assist in the development of targeted treatments to enhance women's reproductive capability when it is desired.AbbreviationsCL: corpus luteum; P4: progesterone; E2: estradiol; PDG: pregnanediol 3-glucoronide; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin releasing hormone; BMI: body mass index; qrtPCR: quantitative real-time PCR; PGR: progesterone receptor; ART: assisted reproductive technology; IVF: in vitro fertilization; HPO: hypothalamic-pituitary-ovarian axis; MMPs: matrix metalloproteinases Gene symbols: LH receptor (LHGCR); cholesterol side-chain cleavage enzyme (CYP11A1); 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2); steroidogenic acute regulatory protein (STAR); LDL receptor (LDLR); scavenger receptor B1 (SCARB1); ATP-binding cassette sub-family A member 1 (ABCA1); ATP-binding cassette sub-family G member 1 (ABCG1); apolipoprotein A (APOA1); 24 dehydrocholesterol reductase (DHCR24); 3-hydroxy-3-methylglytaryl-CoA reductase (HMGCR); vascular endothelial growth factor A (VEGFA); vascular endothelial growth factor C (VEGFC); vascular endothelial growth factor receptor 1 (VEGFR1); and TIMP metallopeptidase inhibitor 1 (TIMP1); amphiregulin (AREG); epiregulin (EREG); CCAAT/enhancer binding protein alpha (CEBPBA); cAMP responsive element binding protein 3-like 1 (CREB3L1); ADAM metallopeptidase with thrombospodin type 1 motif 1 (ADAMTS1); matrix metallopeptidase 9 (MMP9); cytochrome b-245 beta polypeptide (CYBB or NOX2); NADH oxidase (NCF2 or NOXA2); Fc fragment of IgG receptor IIb (FCGR2B); Fc fragment of IgG receptor IIb (FCGR2C); ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1); RAB27A member RAS oncofamily (RAB27A); hydroxyprostaglandin dehydrogenase (HPGD); prostaglandin-endoperoxidase synthase 1 (PTGS1); integrin B2 (ITGB2); leukotriene A4 hydrolase (LTA4H); radixin (RDX); ezrin (EZR); nuclear receptor subfamily 5 group A member 2 (NR5A2).

Project description:BackgroundDespite significant advances in our understanding of the pathophysiology of preeclampsia (PE), there are still many unknowns and controversies in the field. Women undergoing frozen-thawed embryo transfer (FET) to a hormonally prepared endometrium have been found to have an unexpected increased risk of PE compared to women who receive embryos in a natural FET cycle. The differences in risk have been hypothesized to be related to the absence or presence of a functioning corpus luteum (CL).Objective and rationaleTo evaluate the literature on secretory products of the CL that could be essential for a healthy pregnancy and could reduce the risk of PE in the setting of FET.Search methodsFor this review, pertinent studies were searched in PubMed/Medline (updated June 2020) using common keywords applied in the field of assisted reproductive technologies, CL physiology and preeclampsia. We also screened the complete list of references in recent publications in English (both animal and human studies) on the topics investigated. Given the design of this work as a narrative review, no formal criteria for study selection or appraisal were utilized.OutcomesThe CL is a major source of multiple factors regulating reproduction. Progesterone, estradiol, relaxin and vasoactive and angiogenic substances produced by the CL have important roles in regulating its functional lifespan and are also secreted into the circulation to act remotely during early stages of pregnancy. Beyond the known actions of progesterone and estradiol on the uterus in early pregnancy, their metabolites have angiogenic properties that may optimize implantation and placentation. Serum levels of relaxin are almost undetectable in pregnant women without a CL, which precludes some maternal cardiovascular and renal adaptations to early pregnancy. We suggest that an imbalance in steroid hormones and their metabolites and polypeptides influencing early physiologic processes such as decidualization, implantation, angiogenesis and maternal haemodynamics could contribute to the increased PE risk among women undergoing programmed FET cycles.Wider implicationsA better understanding of the critical roles of the secretory products of the CL during early pregnancy holds the promise of improving the efficacy and safety of ART based on programmed FET cycles.

Dataset Information

Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice.

Publications

Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice.

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