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Foxl2 functions in sex determination and histogenesis throughout mouse ovary development, analyzed by Agilent arrays

ABSTRACT: Partial loss of function of the transcription factor FOXL2 leads to premature ovarian failure in women. In animal models, Foxl2 is required for maintenance, and possibly induction, of female sex determination independently of other critical genes, i.e., Rspo1 and Wnt4. Here we report expression profiling of mouse ovaries that lack Foxl2 alone or in combination with Wnt4 or Kit/c-Kit, to identify ovarian targets of Foxl2 that, along with some testis genes, were dysregulated during embryonic development. Loss of one copy of Foxl2 revealed strong gene dosage sensitivity, with molecular anomalies that were milder but resembled ovaries lacking both Foxl2 alleles. Furthermore, a Foxl2 transgene disrupted embryonic testis differentiation and increased the levels of key female markers. The results, including a comprehensive principal component analysis of published microarray datasets 1) support the proposal of dose-dependent Foxl2 function and anti-testis action throughout ovary differentiation; and 2) identify candidate genes for a role in sex determination independent of FOXL2 (notably, the transcription factor, ZBTB7C) and in the generation of the ovarian reserve downstream of it (e.g., the cadherin-domain protein CLSTN2, or the sphingomyelin synthase, SGMS2). The gene inventory provides a framework to analyze the genetic bases of ovarian development and female fertility. Keywords: reference design

ORGANISM(S): Mus musculus

PROVIDER: GSE12942 | GEO | 2009/06/24

SECONDARY ACCESSION(S): PRJNA114257

REPOSITORIES: GEO

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Foxl2 functions in sex determination and histogenesis throughout mouse ovary development, analyzed by Agilent arrays

Project description:Partial loss of function of the transcription factor FOXL2 leads to premature ovarian failure in women. In animal models, Foxl2 is required for maintenance, and possibly induction, of female sex determination independently of other critical genes, i.e., Rspo1 and Wnt4. Here we report expression profiling of mouse ovaries that lack Foxl2 alone or in combination with Wnt4 or Kit/c-Kit, to identify ovarian targets of Foxl2 that, along with some testis genes, were dysregulated during embryonic development. Loss of one copy of Foxl2 revealed strong gene dosage sensitivity, with molecular anomalies that were milder but resembled ovaries lacking both Foxl2 alleles. Furthermore, a Foxl2 transgene disrupted embryonic testis differentiation and increased the levels of key female markers. The results, including a comprehensive principal component analysis of published microarray datasets 1) support the proposal of dose-dependent Foxl2 function and anti-testis action throughout ovary differentiation; and 2) identify candidate genes for a role in sex determination independent of FOXL2 (notably, the transcription factor, ZBTB7C) and in the generation of the ovarian reserve downstream of it (e.g., the cadherin-domain protein CLSTN2, or the sphingomyelin synthase, SGMS2). The gene inventory provides a framework to analyze the genetic bases of ovarian development and female fertility. Keywords: reference design Comparison of Foxl2+/+,+/- and -/- whole ovaries at 2 timepoints delineating follicle formation

2010-05-17 | E-GEOD-12942 | biostudies-arrayexpress

Foxl2 functions in sex determination and histogenesis throughout mouse ovary development, analyzed by Affymetrix arrays

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Transcription profiling of mouse ovaries lacking Foxl2, Wnt4 or Kit and wild type ovaries and testes

Project description:Comparison of Foxl2-null ovaries to wildtype ovaries, ovaries lacking Wnt4 or Kit, or testes, throughout mouse development. The goal of this study was to identify early Foxl2 target genes as well as other ovarian, anti-testis genes that may act independently of Foxl2. Experiment Overall Design: We studied 43 samples over 15 conditions to cover a wide range of wiltype and pathological states showing highly divergent alterations of cell type composition. This was meant to identify the most specific, cell context-independent targets of Foxl2.

2009-07-05 | E-GEOD-12905 | biostudies-arrayexpress

Sexual cell fate reprogramming in the ovary by DMRT1

Project description:Transcription factors related to the insect sex determination gene Doublesex (DMRT proteins) control sex determination and/or sexual differentiation in diverse metazoans. They also are implicated in transitions between sex-determining mechanisms during vertebrate evolution. In mice Dmrt1 is required for male gonadal differentiation in somatic cells and germ cells. DMRT1 also maintains male gonadal sex: its loss, even in adults, can trigger sexual fate reprogramming in which male Sertoli cells transdifferentiate into their female equivalents - granulosa cells - and testicular tissue reorganizes to a more ovarian morphology. Here we use a conditional Dmrt1 transgene to show that Dmrt1 is not only necessary but also sufficient to specify male cell identity in the mouse gonad. DMRT1 expression in the ovary silenced the female sex-maintenance gene Foxl2 and reprogrammed juvenile and adult granulosa cells into Sertoli-like cells, triggering formation of structures resembling male seminiferous tubules. DMRT1 can silence Foxl2 even in the absence of the testis-determining genes Sox8 and Sox9. mRNA profiling found that DMRT1 activates many testicular genes and downregulates ovarian genes and single cell RNA-seq in transdifferentiating cells identified dynamically expressed candidate mediators of this process. Strongly upregulated genes were highly enriched on chromosome X, consistent with sexually antagonistic functions. This study provides an in vivo example of single gene reprogramming of cell sexual identity. Our findings suggest a reconsideration of mechanisms involved in human disorders of sexual development (DSD) and empirically support evolutionary models where loss or gain of Dmrt1 function promotes establishment of new vertebrate sex determination systems. RNA-Seq (3 conditions, 2 replicates per condition) and Single Cell RNA-Seq (68 individual cells and 1 bulk cell sample)

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Sexual cell fate reprogramming in the ovary by DMRT1

2015-02-27 | GSE64960 | GEO

RUNX1 safeguards the identity of the fetal ovary through an interplay with FOXL2

Project description:Sex determination of the gonads begins with fate specification of gonadal supporting cells into either ovarian granulosa cells or testicular Sertoli cells. This process of fate specification hinges on a balance of transcriptional control. We discovered that the transcription factor RUNX1 is enriched in the fetal ovary in rainbow trout, turtle, mouse, and human. In the mouse, RUNX1 marks the supporting cell lineage and becomes granulosa cell-specific as the gonads differentiate. RUNX1 plays complementary/redundant roles with FOXL2 to maintain fetal granulosa cell identity, and combined loss of RUNX1 and FOXL2 results in masculinization of the fetal ovaries. To determine whether interplay between RUNX1 and FOXL2 occurs at the chromatin level, we performed genome-wide analysis of RUNX1 chromatin occupancy in E14.5 ovaries. The top de novo motif identified in RUNX1 ChIP-seq matched the RUNX motif. We found that RUNX1 chromatin occupancy was partially overlapping with FOXL2 chromatin occupancy in fetal ovaries.

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Expression data from Foxl2 wild-type and mutant ovaries and testes

Project description:Foxl2 is a forkhead transcription factor expressed only in the female, but not in the male gonad. We have created mice homozygous mutant for the Foxl2 gene (KO) as well as mice carrying a conditional mutant Foxl2 allele (floxed). The expression profiles of conventional Foxl2 knockout and wildtype ovaries were compared at P3, using the Affy Mouse Genome 430 2.0 Array. Adult wildtype and conditional mutant (Foxl2 floxed x RosaCre-EBD treated with tamoxifen) ovaries were compared to adult wildtype testes using the Affymetrix Mouse Gene 1.0 ST Array. Both experiments (KO/WT P3 and Mutant/WT/Testis Adult were also compared to each other.)

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Microarray gene expression profiles from mature gonad tissues of Atlantic Bluefin Tuna, Thunnus Thynnus in the Gulf of Mexico

Project description:The aim of this investigation was to compare transcription profiles from the ovaries and testes of mature T. thynnus to establish sex specific variations underlying their reproductive physiology. Two condition experiment, testis vs ovarian tissue. Biological replicates 4 male testes and 4 female ovaries.

2012-02-20 | E-GEOD-34084 | biostudies-arrayexpress

Genome wide identification of FOXL2 binding sites in mouse fetal ovaries

Project description:The identity of the gonads is determined by which fate, ovarian granulosa cell or testicular Sertoli cell, the bipotential somatic cell precursors choose to follow. In most vertebrates, the fate of granulosa cells is controlled by a conserved regulator FOXL2. To understand how FOXL2 elicits its fate-determining action, we performed genome-wide analysis of FOXL2 chromatin occupancy in fetal ovaries. Combining genome-wide analysis of FOXL2 binding in the fetal ovary with transcriptomic analyses of Foxl2 gain-of-function and Foxl2 loss-of-function models, we identified potential pathways responsible for the feminizing action of FOXL2. Finally, comparison of FOXL2 genome-wide occupancy in the fetal ovary with testis-determining factor SOX9 genome-wide occupancy in the fetal testis revealed extensive overlaps, implying that antagonistic signals between FOXL2 and SOX9 occur at the chromatin level.

2019-03-21 | GSE110093 | GEO

Reprogramming of somatic cell fate in fetal mouse testis by FOXL2

Project description:From fish to human, FOXL2 is considered one of the most conserved markers of ovarian granulosa cell identity. To determine if the sole expression of FOXL2 can determine ovarian differentiation, we created a mouse model that allows the conditional expression of FOXL2. Rosa26-CAG-LSL-Foxl2 mice were crossed to Sf1-Cre mice to induce the expression of FOXL2 in the SF1+ somatic cells of the fetal gonads.When FOXL2 was induced in the somatic cells of the undifferentiated testis, the Sertoli cells and consequently the other cell lineages composing the fetal gonads were feminized, resulting in a partial testis-to-ovary sex reversal We created a mouse genetic model that conditionaly express FOXL2 in the somatic cells of the fetal gonads. All embryos used in this study resulted from the crossing between Rosa26-CAG-LSL-Foxl2+/f and Sf1-cre+/Tg mice. XX and XY fetal gonads were collected at embryonic day E14.5. This microarray analysis led to the identification of the genes misregulated upon ectopic induction of FOXL2 in the fetal testis, and showed that FOXL2 expression resulted in feminization of both somatic and germ cells of the fetal gonad.

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