Lim Homeobox Gene, LHX8, Is Essential for Mouse Oocyte Differentiation and Survival
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE11897 | GEO | 2008/06/26
SECONDARY ACCESSION(S): PRJNA105729
REPOSITORIES: GEO
Similar Datasets
Project description:Lhx8 is a member of the LIM-homeobox transcription factor family and preferentially expressed in oocytes and germ cells within the mouse ovary. We discovered that Lhx8 knockout females lose oocytes within 7 days after birth. At the time of birth, histological examination shows that Lhx8 deficient (Lhx8(-/-)) ovaries are grossly similar to the newborn wild type ovaries. Lhx8(-/-) ovaries fail to maintain the primordial follicles and the transition from primordial to growing follicles does not occur. Lhx8(-/-) ovaries misexpress oocyte-specific genes such as Gdf9, Pou5f1, and Nobox. Very rapid loss of oocytes may partly be due to drastic the down-regulation of Kit and Kitl in Lhx8(-/-) ovaries. We compared Lhx8(-/-) and wild-type ovaries using Affymetrix 430 2.0 microarray platform. Eighty (44%) of 180 of the genes down-regulated more than 5-fold in Lhx8(-/-) ovaries were preferentially expressed in oocytes, whereas only 3 (2%) of 146 genes up-regulated more than 5-fold in the absence of Lhx8 were preferentially expressed in oocytes. In addition, the comparison of genes regulated in Lhx8(-/-) and Nobox(-/-) newborn ovaries discovered a common set of 34 genes whose expression level is affected in both Lhx8 and Nobox deficient mice. Our findings show that Lhx8 is a critical factor for maintenance and differentiation of the oocyte during early oogenesis and it acts in part by down-regulating the Nobox pathway. This SuperSeries is composed of the following subset Series: GSE7774: Transcriptional changes in Lhx8 Null newborn mouse ovaries GSE7775: Microarray Analyses of Newborn Mouse Ovaries Lacking Nobox GSE7776: Ovarian Transcript Expression in Newborn Mouse Refer to individual Series
2008-06-25 | E-GEOD-11897 | biostudies-arrayexpress
Project description:Nobox is a homeobox gene expressed in oocytes and critical in oogenesis. Nobox deficiency leads to rapid loss of postnatal oocytes. Early oocyte differentiation is poorly understood. We hypothesized that lack of Nobox perturbs global expression of genes preferentially expressed in oocytes as well as microRNAs. We compared Nobox knockout and wild type ovaries using Affymetrix 430 2.0 microarray platform. We discovered that 28 out of 38 (74%) of the genes down-regulated more than five fold in the absence of Nobox were preferentially expressed in oocytes, while only 5 out of 33 (15%) of genes up-regulated more than five fold in the absence of Nobox, were preferentially expressed in oocytes. Protein binding microarray helped identify nucleotide motifs that NOBOX binds, and that several down-regulated genes contain within putative promoter regions. MicroRNA population in newborn ovaries deficient of Nobox, was largely unaffected. Genes whose proteins are predicted to be secreted, but previously unknown to be significantly expressed in early oogenesis, were down regulated in Nobox knockouts and included astacin-like metalloendopeptidase (Astl), Jagged 1 (Jag1), oocyte secreted protein 1 (Oosp1), fetuin beta (Fetub) and R-spondin 2 (Rspo2). In addition, pluripotency associated genes, Pou5f1 and Sall4 are drastically down-regulated in Nobox deficient ovaries, while testes determining gene Dmrt1 is over-expressed. Our findings indicate that Nobox is likely an activator of oocyte-specific gene expression, and suggest that oocyte plays an important role in suppressing expression of male determining genes such as Dmrt1. Experiment Overall Design: Newborn ovaries were pooled separately from wild type and Nobox -/- animals and total RNA isolated using RNeasy mini kit (Qiagen, CA). Newborn ovaries were collected within 12 hours of delivery. Animal experimentation was approved by the Institutional Animal Care and Use Committee of Baylor College of Medicine. Three independently pooled RNA samples from wild type and Nobox -/- newborn ovaries were used to generate biotinylated cRNA. Biotinylated cRNA was hybridized to GeneChip Mouse Expression Set 430 2.0 (Affymetrix, Inc.). Since three independent experiments were performed from three independent pools of wild type and Nobox -/- RNA, signal intensities for particular genes were averaged between the three chips and ratio of the wild type over knockout signal calculated. Signal less than 100 was considered background. The raw data in the Affymetrix CEL files were normalized by the RMA method (robust multi-array analysis) [15, 16]. Then the null hypothesis was tested that there is no significant changes in gene expression between the treatment pairs. This was done by LIMMA [17] and the pooled local error (LPE) method [18]. The raw pvalues were adjusted by the Benjamini-Hochberg method for the false discovery rate of 5% [19]. We used DAVID database [20] to aid in functional annotation of genes affected by Nobox deficiency
2008-06-15 | E-GEOD-7775 | biostudies-arrayexpress
Project description:Nobox is a homeobox gene expressed in oocytes and critical in oogenesis. Nobox deficiency leads to rapid loss of postnatal oocytes. Early oocyte differentiation is poorly understood. We hypothesized that lack of Nobox perturbs global expression of genes preferentially expressed in oocytes as well as microRNAs. We compared Nobox knockout and wild type ovaries using Affymetrix 430 2.0 microarray platform. We discovered that 28 out of 38 (74%) of the genes down-regulated more than five fold in the absence of Nobox were preferentially expressed in oocytes, while only 5 out of 33 (15%) of genes up-regulated more than five fold in the absence of Nobox, were preferentially expressed in oocytes. Protein binding microarray helped identify nucleotide motifs that NOBOX binds, and that several down-regulated genes contain within putative promoter regions. MicroRNA population in newborn ovaries deficient of Nobox, was largely unaffected. Genes whose proteins are predicted to be secreted, but previously unknown to be significantly expressed in early oogenesis, were down regulated in Nobox knockouts and included astacin-like metalloendopeptidase (Astl), Jagged 1 (Jag1), oocyte secreted protein 1 (Oosp1), fetuin beta (Fetub) and R-spondin 2 (Rspo2). In addition, pluripotency associated genes, Pou5f1 and Sall4 are drastically down-regulated in Nobox deficient ovaries, while testes determining gene Dmrt1 is over-expressed. Our findings indicate that Nobox is likely an activator of oocyte-specific gene expression, and suggest that oocyte plays an important role in suppressing expression of male determining genes such as Dmrt1. Keywords: Genetic Modification
2007-10-31 | GSE7775 | GEO
Project description:Germ-cell transcription factors control gene networks that regulate primordial follicle formation and oocyte differentiation during early, postnatal mouse oogenesis. Taking advantage of gene-edited mice lacking transcription factors expressed in female germ cells, we analyzed global gene expression profiles in perinatal ovaries from wildtype, FiglaNull, Lhx8Null and SohlhNull mice. Figla deficiency dysregulates expression of meiosis-related genes (e.g., Sycp3, Rad51 and Msy2) and a variety of genes (e.g., Nobox, Lhx8, Taf4b, Sohlh1, Sohlh2 and Gdf9) associated with oocyte growth and differentiation. The absence of FIGLA significantly impedes meiotic progression, causes DNA damage and results in oocyte apoptosis. Moreover, we find that FIGLA and other transcriptional regulators (e.g., NOBOX, LHX8, SOHLH1 and SOHLH2) are co-expressed in the same subset of germ cells in perinatal ovaries and Figla ablation dramatically disrupts KIT, NOBOX, LHX8, SOHLH1 and SOHLH2 expression. In addition, not only do FIGLA, SOHLH1 and LHX8 cross-regulate each other, they also cooperate by direct interaction with each during early oocyte development and share downstream gene targets. Thus, our findings substantiate a major role for FIGLA, LHX8 and SOHLH1 as multifunctional regulators of networks necessary for oocyte maintenance and differentiation during early folliculogenesis.
2019-11-06 | GSE139966 | GEO
Project description:Serine/arginine-rich splicing factor 1 (SRSF1; previously SF2/ASF) is a pivotal posttranscriptional regulator of gene expression in various biological processes. However, the physiological roles and mechanism of SRSF1 in mouse early-stage oocytes remain elusive. Here we show that SRSF1 is essential for primordial follicle formation and number determination during meiotic prophase I. The conditional knockout of Srsf1 in mouse oocytes impairs primordial follicle formation and leads to primary ovarian insufficiency (POI). Oocyte-specific genes (e.g., LHX8, NOBOX, SOHLH1, SOHLH2, FIGLA, KIT, JAGGED1, and RAC1) that regulate primordial follicle formation are suppressed in newborn Stra8-GFPCre Srsf1Fl/Fl (cKO) mouse ovaries. However, meiotic defects are the leading cause of abnormal primordial follicle formation. In cKO mouse ovaries, immunofluorescence results suggest that the failure of synapsis and the inability to undergo recombination result in fewer homologous DNA crossovers (COs). Moreover, SRSF1 directly binds and regulates the expression of the POI-related genes Six6os1 and Msh5 via alternative splicing to implement the meiotic prophase I program. Altogether, our data reveal a critical role of the SRSF1-mediated posttranscriptional regulatory mechanism in the mouse oocyte meiotic prophase I program, which provides a framework to elucidate molecular mechanisms of the posttranscriptional network underlying primordial follicle formation.
2023-02-06 | GSE198205 | GEO
Project description:Lhx8 is a homeobox gene expressed in oocytes and critical in oogenesis. Lhx8 deficiency leads to rapid loss of postnatal oocytes. Early oocyte differentiation is poorly understood. We hypothesized that lack of Lhx8 perturbs global expression of genes preferentially expressed in oocytes. We compared Lhx8 knockout and wild type ovaries using Affymetrix 430 2.0 microarray platform. Keywords: Genetic Modification
2007-10-31 | GSE7774 | GEO
Project description:Following proliferation of oogonia inmammals, great numbers of germ cells are discarded, primarily by apoptosis, while the remainder form primordial follicles (the ovarian reserve) that determine fertility and reproductive lifespan. More massive, rapid, and essentially total loss of oocytes, however, occurs when the transcription factor Lhx8 is ablated—though the cause and mechanism of germ cell loss from the Lhx8-/- ovaries has been unknown. We found that Lhx8−/− ovaries maintain the same number of germ cells throughout embryonic development; rapid decrease in the pool of oocytes starts shortly before birth. The loss results from activation of autophagy, which becomes overwhelming within the first postnatal week, with extracellular matrix proteins filling the space previously occupied by follicles to produce a fibrotic ovary. Associated with this process, as early as a few days before birth, Lhx8-/- oocytes failed to repair DNA damage—which normally occurs when meiosis is initiated during embryonic development; and DNA damage repair genes were downregulated throughout the oocyte short lifespan. Based on gene expression analyses and morphological changes, we propose a model in which lineage-restricted failure of DNA repair triggers germ cell autophagy, causing premature depletion of the ovarian reserve in Lhx8-/- mice
2019-01-22 | GSE109473 | GEO
Project description:Lhx8 is a homeobox gene expressed in oocytes and critical in oogenesis. Lhx8 deficiency leads to rapid loss of postnatal oocytes. Early oocyte differentiation is poorly understood. We hypothesized that lack of Lhx8 perturbs global expression of genes preferentially expressed in oocytes. We compared Lhx8 knockout and wild type ovaries using Affymetrix 430 2.0 microarray platform. Experiment Overall Design: Each array was hybridized with cRNA produced from pooled total RNA from at least 25 specimens. The experiment was performed with 3 replicates. The results from these three arrays was compared to arrays hybridized with cRNA produced from pooled total RNA from at least 25 wild type specimens of the same genetic background.
2008-06-15 | E-GEOD-7774 | biostudies-arrayexpress
Project description:In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 months to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP cytokines in the ovary. In addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation and female fertility. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.
2024-04-30 | GSE253194 | GEO
Project description:Primordial follicle assembly is a process that occurs in the embryonic or early post natal ovary in which oocyte nests break down to form individual primordial follicles. The size of this initial pool of primordial follicles in part determines the reproductive lifespan of the female. Connective tissue growth factor (CTGF) was identified as a potential regulatory candidate for this process in a previous microarray analysis of follicle development. The current study examines the effects of CTGF and associated transforming growth factor beta 1 (TGFbeta-1) on follicle assembly. Ovaries were removed from newborn rat pups and placed in an organ culture system for two days to measure the effect of these factors on follicle assembly. In addition, ovaries were cultured and treated for ten days to determine the potential of CTGF and TGFbeta-1 to manipulate the primordial follicle pool size over a longer developmental time period. The ovaries treated with CTGF for two days were found to have an increased proportion of assembled follicles. TGFbeta-1 had no effect on primordial follicle assembly and in combination with CTGF decreased oocyte number in the ovary after two days of culture. Over ten days of treatment only the combined treatment of CTGF and TGFbeta-1 was found to cause an increase in the proportion of assembled follicles. Interestingly, treatment with TGFbeta-1 alone resulted in fewer total oocytes in the ovary and decreased the primordial follicle pool size after ten days of culture. Observations indicate that CTGF alone or in combination with TGFbeta-1 stimulates primordial follicle assembly and TGFbeta-1 can decrease the primordial follicle pool size. CTGF was found to regulate the ovarian transcriptome during primordial follicle assembly and an integrative network of genes was identified. CTGF is one of the first growth factors shown to promote primordial follicle assembly, while TGFbeta-1 is one of the first factors shown to decrease the primordial follicle pool size. These observations suggest the possibility of manipulating primordial follicle pool size and influencing female reproductive lifespan. We used microarrays to determine genes expressed differentially between control and CTGF (connective tissue growth factor) treated P0 ovary RNA samples from 3 control groups are compared to 3 CTGF treated ovary groups
2010-09-16 | E-GEOD-22096 | biostudies-arrayexpress