stem cell marker/////
Ovary and fimbrial stem cells: biology, niche and cancer origins. Ng A et al. (2015) The mammalian ovary is covered by a single-layered epithelium that undergoes rupture and remodelling following each ovulation. Although resident stem cells are presumed to be crucial for this cyclic regeneration, their identity and mode of action have been elusive. Surrogate stemness assays and in vivo fate-mapping studies using recently discovered stem cell markers have identified stem cell pools in the ovary and fimbria that ensure epithelial homeostasis. Recent findings provide insights into intrinsic mechanisms and local extrinsic cues that govern the function of ovarian and fimbrial stem cells. These discoveries have advanced our understanding of stem cell biology in the ovary and fimbria, and lay the foundations for evaluating the contribution of resident stem cells to the initiation and progression of human epithelial ovarian cancer.//////////////////
NCBI Summary:
The protein encoded by this gene belongs to the aldehyde dehydrogenase family. Aldehyde dehydrogenase is the next enzyme after alcohol dehydrogenase in the major pathway of alcohol metabolism. There are two major aldehyde dehydrogenase isozymes in the liver, cytosolic and mitochondrial, which are encoded by distinct genes, and can be distinguished by their electrophoretic mobility, kinetic properties, and subcellular localization. This gene encodes the cytosolic isozyme. Studies in mice show that through its role in retinol metabolism, this gene may also be involved in the regulation of the metabolic responses to high-fat diet. [provided by RefSeq, Mar 2011]
ALDH1A1 provides a source of meiosis-inducing retinoic acid in mouse fetal ovaries. Bowles J et al. (2016) Substantial evidence exists that during fetal ovarian development in mammals, retinoic acid (RA) induces germ cells to express the pre-meiotic marker Stra8 and enter meiosis, and that these effects are prevented in the fetal testis by the RA-degrading P450 enzyme CYP26B1. Nonetheless, the role of RA has been disputed principally because germ cells in embryos lacking two major RA-synthesizing enzymes, ALDH1A2 and ALDH1A3, remain able to enter meiosis. Here we show that a third RA-synthesizing enzyme, ALDH1A1, is expressed in fetal ovaries, providing a likely source of RA in the absence of ALDH1A2 and ALDH1A3. In ovaries lacking ALDH1A1, the onset of germ cell meiosis is delayed. Our data resolve the conundrum posed by conflicting published data sets and reconfirm the model that meiosis is triggered by endogenous RA in the developing ovary.//////////////////
Meiosis initiation in the human ovary requires intrinsic retinoic acid synthesis. Le Bouffant R et al. BACKGROUND The initiation of meiosis is crucial to fertility. While extensive studies in rodents have enhanced our understanding of this process, studies in human fetal ovary are lacking. METHODS We used RT-PCR and immunohistochemistry to investigate expression of meiotic factors in human fetal ovaries from 6 to 15 weeks post fertilization (wpf) and developed an organ culture model to study the initiation of human meiosis. RESULTS We observed the first meiotic cells at 11 wpf, when STRA8, SPO11 and DMC1 are first expressed. In culture, meiosis initiation is observed in 10 and 11 wpf ovaries and meiosis is maintained by addition of fetal calf serum. Meiosis is stimulated, compared with control, by retinoic acid (RA) (P < 0.05). No major change occurred in mRNA for CYP26B1, the RA-degrading enzyme proposed to control the timing of meiosis in mice. We did, however, observe increased mRNA levels for ALDH1A1 in human ovary when meiosis began, and evidence for a requirement to synthesize RA and thus sustain meiosis. Indeed, ALDH inhibition by citral prevented the appearance of meiotic cells. Finally, 8 wpf ovaries (and earlier stages) were unable to initiate meiosis whatever the length of culture, even in the presence of RA and serum. However, when human germ cells from 8 wpf ovaries were placed in a mouse ovarian environment, some did initiate meiosis. CONCLUSIONS Our data indicate that meiosis initiation in the human ovary relies partially on RA, but that the progression and regulation of this process appears to differ in many aspects from that described in mice.
Expression regulated by
FSH, LH
Comment
De novo-synthesized retinoic acid in ovarian antral follicles enhances FSH-mediated ovarian follicular cell differentiation and female fertility. Kawai T et al. (2016) Retinoic acid (RA) is the active form of vitamin A and is synthesized from retinol by two key enzymes, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). As the physiological precursor of RA, retinol impacts female reproductive functions and fertility. The expression of Adh1 and Adh5 as well as Aldh1a1 and Aldh1a7 are significantly increased in ovaries of mice treated with equine chorionic gonadotropin (eCG/FSH). The RA receptor, RAR is expressed and localized in granulosa cells and is activated by endogenous RA as indicated by LacZ expression in granulosa cells of RARE-LacZ transgenic mice (RA reporter mice). Co-injection of the ADH inhibitor, 4-methylpyrazole (4MP), with eCG significantly decreases the number and developmental competence of oocytes ovulated in response to human chorionic gonadotropin (hCG/LH) as compared with controls. Injections of RA completely reverse the effects of the inhibitor of ovulation and oocyte development. When mice were fed a retinol-free, vitamin A deficient (VAD) diet that significantly reduced serum levels of retinol, the expression of the LH receptor (Lhcgr) was significantly lower in ovaries of the VAD mice and injections of hCG failed to induce genes controlling ovulation. These results indicate that ovarian de novo biosynthesis of RA is required for follicular expression of Lhcgr in granulosa cells and their ability to respond to the ovulatory LH surge.//////////////////
GATA Depletion Impacts Insulin-like Growth Factor 1 mRNA and Protein Levels in Luteinizing Porcine Granulosa Cells. Lavoie HA et al. GATA4 and GATA6 are zinc finger transcription factors that regulate specific genes involved in steroidogenesis. Using RNAi-mediated reduction of GATA4 and/or GATA6 with microarray analysis we aimed to identify novel GATA target genes in luteinizing porcine granulosa cells under vehicle- and cyclic AMP-treated conditions. Microarray identified IGF1 mRNA to be cAMP- and GATA-responsive and real-time PCR demonstrated that the cAMP-induced increase in IGF1 mRNA was reduced under conditions of GATA6 and GATA4+GATA6 depletion, but not by GATA4 depletion. Insulin-like growth factor 1 protein levels in media were also decreased by GATA6 or GATA4+GATA6 reduction. IGFBP2 and IGFBP4 mRNAs were increased and IGFBP5 mRNA decreased with vehicle and cAMP treatment under GATA4+GATA6 RNAi conditions. GATA6 reduction alone increased basal IGFBP4, decreased IGFBP5 with both vehicle and cAMP, and GATA4 reduction alone lowered cAMP IGFBP5 levels with cAMP. No changes in IGFBP3 mRNA were observed with GATA reduction relative to the Control RNAi condition. IGFBP2-5 protein levels in media as assessed by Western ligand blotting were not altered by GATA reduction. Electromobility gel shift assays with two GATA-containing oligonucleotides of the IGF1 5'-regulatory region showed GATA4 and GATA6 could bind the more proximal GATA-B site. These studies indicate that although GATA4 and GATA6 can bind the porcine IGF1 5'-region, that GATA6 is functionally most important for cAMP-stimulated mRNA levels. Using microarray, we identified other mRNAs that were altered by GATA-reduced conditions including ALDH1, DIO2, and EDNRB. Our findings further support GATA as a coordinator of endocrine/paracrine/autocrine signals in the ovary.
Ovarian localization
Primordial Germ Cell
Comment
Global gene expression analysis in fetal mouse ovaries with and without meiosis and comparison of selected genes with meiosis in the testis. Olesen C et al. In order to identify novel genes involved in early meiosis and early ovarian development in the mouse, we used microarray technology to compare transcriptional activity in ovaries without meiotic germ cells at embryonic age 11.5 (E11.5) and E13.5 ovaries with meiosis. Overall, 182 genes were differentially expressed; 134 were known genes and 48 were functionally uncharacterized. A comparison of our data with the literature associated, for the first time, at least eight of the known genes with female meiosis/germ cell differentiation (Aldh1a1, C2pa, Tex12, Stk31, Lig3, Id4, Recql, Piwil2). These genes had previously only been described in spermatogenesis. The microarray also detected an abundance of vesicle-related genes of which four were upregulated (Syngr2, Stxbp1, Ric-8, SytIX) and one (Myo1c) was downregulated in E13.5 ovaries. Detailed analysis showed that the temporal expression of SytIX also coincided with the first meiotic wave in the pubertal testis. This is the first time that SytIX has been reported in non-neuronal tissue. Finally, we examined the expression of one of the uncharacterized genes and found it to be gonad-specific in adulthood. We named this novel transcript 'Gonad-expressed transcript 1' (Get-1). In situ hybridization showed that Get-1 was expressed in meiotic germ cells in both fetal ovaries and mature testis. Get-1 is therefore a novel gene in both male and female meiosis.
Follicle stages
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary. Minkina A et al. (2017) Retinoic acid (RA) is a potent inducer of cell differentiation and plays an essential role in sex-specific germ cell development in the mammalian gonad. RA is essential for male gametogenesis and hence fertility. However, RA can also disrupt sexual cell fate in somatic cells of the testis, promoting transdifferentiation of male Sertoli cells to female granulosa-like cells when the male sexual regulator Dmrt1 is absent. The feminizing ability of RA in the Dmrt1 mutant somatic testis suggests that RA might normally play a role in somatic cell differentiation or cell fate maintenance in the ovary. To test for this possibility we disrupted RA signaling in somatic cells of the early fetal ovary using three genetic strategies and one pharmaceutical approach. We found that deleting all three RA receptors (RARs) in the XX somatic gonad at the time of sex determination did not significantly affect ovarian differentiation, follicle development, or female fertility. Transcriptome analysis of adult triple mutant ovaries revealed remarkably little effect on gene expression in the absence of somatic RAR function. Likewise, deletion of three RA synthesis enzymes (Aldh1a1-3) at the time of sex determination did not masculinize the ovary. A dominant-negative RAR transgene altered granulosa cell proliferation, likely due to interference with a non-RA signaling pathway, but did not prevent granulosa cell specification and oogenesis or abolish fertility. Finally, culture of fetal XX gonads with an RAR antagonist blocked germ cell meiotic initiation but did not disrupt sex-biased gene expression. We conclude that RA signaling, although crucial in the ovary for meiotic initiation, is not required for granulosa cell specification, differentiation, or reproductive function.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary. Chassot AA et al. (2020) In mammals, the timing of meiosis entry is regulated by signals from the gonadal environment. All-trans retinoic acid (ATRA) signaling is considered the key pathway that promotes Stra8 (stimulated by retinoic acid 8) expression and, in turn, meiosis entry. This model, however, is debated because it is based on analyzing the effects of exogenous ATRA on ex vivo gonadal cultures, which not accurately reflects the role of endogenous ATRA. Aldh1a1 and Aldh1a2, two retinaldehyde dehydrogenases synthesizing ATRA, are expressed in the mouse ovaries when meiosis initiates. Contrary to the present view, here, we demonstrate that ATRA-responsive cells are scarce in the ovary. Using three distinct gene deletion models for Aldh1a1;Aldh1a2;Aldh1a3, we show that Stra8 expression is independent of ATRA production by ALDH1A proteins and that germ cells progress through meiosis. Together, these data demonstrate that ATRA signaling is dispensable for instructing meiosis initiation in female germ cells.//////////////////