Foxl2 is required for commitment to ovary differentiation

Ottolenghi, Chris; Omari, Shakib; Garcı́a-Ortiz, José Elı́as; Uda, Manuela; Crisponi, Laura; Forabosco, Antonino; Pilia, Giuseppe; Schlessinger, David

doi:10.1093/hmg/ddi210

Cited by 313 publications

(251 citation statements)

References 45 publications

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“…However, it is known that Foxl2 ablation up-regulates Sox9 expression postnatally. [27] According to these studies, the transcriptional dysregulation of a critical subset of genes suggests that the female sex determination/differentiation program is impaired in double-mutant embryonic ovaries. This would predispose to a ''molecular sex reversal.''…”

Section: Foxl2: a Molecular Actor In The Spotlightmentioning

confidence: 99%

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FOXL2 versus SOX9: A lifelong “battle of the sexes”

Veitia

2010

BioEssays

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Testis determination in most mammals is regulated by a genetic hierarchy initiated by the SRY gene. Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY. Recent studies challenge this view and show that the ovary constantly represses male-specific genes, from embryonic stages to adulthood. Notably, the absence of the crucial ovarian transcription factor FOXL2 (alone or in combination with other factors) induces a derepression of male-specific genes during development, postnatally and, even more interestingly, during adulthood. Strikingly, in the adult, targeted ablation of Foxl2 leads to a molecular transdifferentiation of the supporting cells of the ovary, which acquire cytological and transcriptomic characteristics of the supporting cells of the testes. These studies bring many answers to the field of gonadal determination, differentiation and maintenance, but also open many questions. Keywords:.F OXL2; ovary determination; ovarian maintenance IntroductionGonadal sex determination is a process that implies a unique decision to make a testis or an ovary out of a bipotential primordium. In most mammals, sex determination is equated with testis determination, whereas ovarian determination has been considered a default process. That is, absence of the testisdetermining factor would automatically lead to the development of an ovary (in appropriate conditions). Recent articles challenge this view and show that in the ovary active mechanisms are required to maintain the differentiated state. [1,2] The bipotential gonad is made up of four presumptive cell lineages: germ cells (which have an extraembryonic origin) and three types of somatic cells. The somatic component involves the supporting cell precursors, which will give rise to Sertoli cells in the male or granulosa cells in the female, the steroidogenic precursors, which differentiate into Leydig cells (male) and theca cells (female), and finally the connective tissue cells yielding other important structures. [3] From a genetic perspective, the SRY gene is pivotal in switching on the testis-determining cascade.[4] Indeed, murine Sry transcripts appear in the presumptive Sertoli cells from 10.5 days postcoitum and for about 2 days, at the right moment for testis determination. [5] In other mammals, including man, SRY is expressed from the period of testis determination until adulthood [6]). It seems now that the main task of Sry/SRY is to directly activate the gene Sox9, which also encodes a transcription factor. Recently a gonad-specific enhancer that mediates testis Sox9 expression, called TESCO, has been identified. [7] Indeed, Sry along with the steroidogenic factor 1 (Sf1) binds to multiple elements within the TESCO. Moreover, mutation, co-transfection, and sex-reversal studies suggest the existence of a positive feedback circuit. First, Sf1 and Sry cooperatively up-regulate Sox9 transcription. Then, Sox9 and Sf1 recognize the enhancer to maintain the expression of the former in the absence of Sr...

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Section: Foxl2: a Molecular Actor In The Spotlightmentioning

confidence: 99%

“…Would the results of a conditional mutant differ from those previously obtained? [27] The two major forms of the estrogen receptor, Esr1 (ERalpha) and Esr2 (ERbeta), are expressed in the mouse ovary. However, Esr2/ERbeta is predominantly expressed in granulosa cells (and ERalpha in theca cells [46]).…”

Section: Conclusion and Open Questionsmentioning

confidence: 99%

FOXL2 versus SOX9: A lifelong “battle of the sexes”

Veitia

2010

BioEssays

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“…Follistatin (fst) and inha also display the same early sexually dimorphic expression profile as cyp19a1 and foxl2a. In the mouse, the inactivation of Foxl2 (Ottolenghi et al, 2005), Fst (Jorgez et al, 2004), or Cyp19 (Britt et al, 2002) leads to the development of Sertoli cell tubule-like structures in female gonads. In addition, recent work in the goat (Pannetier et al, 2006) and in the tilapia (Wang et al, 2007) also suggests that Foxl2 may be a direct transcriptional activator of Cyp19.…”

Section: Figmentioning

confidence: 99%

Characterization of early molecular sex differentiation in rainbow trout, Oncorhynchus mykiss

Vizziano

Randuineau²,

Báron³

et al. 2007

Developmental Dynamics

183

171

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Early differentiation in rainbow trout gonads was investigated by expression profiling and in situ hybridization (ISH). Expression of cyp19a1 and fst in females and sox9a1 in males were sexually dimorphic between 32 to 35 days post-fertilization (dpf). After 35 dpf, the differentiation proceeded with sexually dimorphic profiles for sox9a2, dmrt1, cyp11b2.1, amh in males and foxl2a, foxl2b, hsd3b1, inha in females. cyp17a1, cyp11a1, star, nr5a1b increased only after 40 dpf in both sexes with a slightly higher expression in females. cyp19a1 expression was localized in a cluster of somatic cells in the ventral side of female gonads, and sox9a2 and amh in somatic cells surrounding the germ cells, at 28 dpf and thereafter, both in male and female gonads. cyp11b2.1, cyp17a1, and cyp11a1 expressions were only detected in scattered somatic cells in males after 46 dpf. This confirms the early implication of cyp19a1 in trout ovarian differentiation and suggests that early testicular differentiation does not need androgen production. Developmental Dynamics

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“…During early human development, Foxl2 plays a crucial role in female reproduction, especially in differentiation and proliferation of granulosa cells, ovarian development, and maintenance of ovarian function by regulating the transcription of certain target genes , Loffler et al 2003, Pisarska et al 2004, Yao 2005. Because of its expression in the early genital ridge and its inhibitory action on the male differentiation pathway (Ottolenghi et al 2005), Foxl2 is recognized as the earliest sex dimorphic marker of ovarian determination and differentiation in mammals. In mice, it is first detected in the developing ovaries at 13 .…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning of doublesex and mab-3-related transcription factor 1, forkhead transcription factor gene 2, and two types of cytochrome P450 aromatase in Southern catfish and their possible roles in sex differentiation

Liu¹,

Wu²,

Jiao³

et al. 2007

Journal of Endocrinology

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To address the roles of doublesex and mab-3-related transcription factor 1 (Dmrt1), forkhead transcription factor gene 2 (Foxl2), and aromatase in sex differentiation of Southern catfish, the cDNA sequences of these genes were isolated from the gonads. Dmrt1a and Dmrt1b were found to be expressed in the gonads, being higher in the testis. A low expression level of Dmrt1b was also detected in the intestine and kidney of the male. Foxl2 was found to be expressed extensively in the brain (B), pituitary (P), gill and gonads (G), with the highest level in the ovary, indicating the possible involvement of Foxl2 in the B-P-G axis. Cytochrome P450 (Cyp)19b was found to be expressed in the brain, spleen, and gonads, while Cyp19a was only expressed in the gonads and spleen. All-female Southern catfish fry were treated with fadrozole (F), tamoxifen (TAM), and 17b-estradiol (E 2 ) respectively, from 5 to 25 days after hatching (dah).The expression levels of these genes were measured at 65 dah. In the F-, TAM-, and FCTAM-treated groups, Dmrt1a and Dmrt1b were up-regulated in the gonad, whereas Foxl2 and Cyp19a were down-regulated, while the expression of Cyp19b in the gonad remained unchanged. Furthermore, downregulation of Foxl2 and Cyp19b was also detected in the brain.In the E 2 -treated group, Dmrt1a and Dmrt1b were downregulated to an undetectable level in the gonad, whereas Foxl2 and Cyp19b were up-regulated in the brain. Consistent with the observed changes in the expressions of these genes, 56, 70, and 80% sex-reversed male individuals were obtained in the F-, TAM-, and FCTAM-treated groups respectively. These results indicate the significant roles of Dmrt1, Foxl2, and Cyp19 in the sex differentiation of Southern catfish.

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Foxl2 is required for commitment to ovary differentiation

Cited by 313 publications

References 45 publications

FOXL2 versus SOX9: A lifelong “battle of the sexes”

FOXL2 versus SOX9: A lifelong “battle of the sexes”

Characterization of early molecular sex differentiation in rainbow trout, Oncorhynchus mykiss

Molecular cloning of doublesex and mab-3-related transcription factor 1, forkhead transcription factor gene 2, and two types of cytochrome P450 aromatase in Southern catfish and their possible roles in sex differentiation

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