Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development

Uda, Manuela; Ottolenghi, Chris; Crisponi, Laura; García, José Elías; Deiana, Manila; Kimber, Wendy L.; Forabosco, Antonino; Cao, Antonio; Schlessinger, David; Pilia, Giuseppe

doi:10.1093/hmg/ddh124

Cited by 483 publications

(412 citation statements)

References 32 publications

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“…[19,20] XY homozygous animals do not display any defect in testis development and XX Foxl2 À/À mice are phenotypically female, but sterile. [19,20] Indeed, ovaries of KO mice are small, severely disorganized, and primordial Follicles either do not form or do not proceed to further maturation stages. [19,20] Interestingly, germ cells of neither Foxl2 KO mice model seem to be affected during early folliculogenesis.…”

Section: Foxl2: a Molecular Actor In The Spotlightmentioning

confidence: 97%

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: 97%

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

Veitia

2010

BioEssays

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“…Besides MAP3K1, embryonic eyelid closure depends on signals derived from WNT, Sonic hedgehog, BMP/Activin, FGF and EGF (Luetteke et al, 1993;Mine et al, 2005;Gage et al, 2008;Huang et al, 2009). In addition, eyelid closure requires the participation of a number of intracellular signaling kinases, such as JNK, ROCK and CDH1, and nuclear transcription factors, such as c-Jun, Fra-2, FOXL2, SMAD and GRHL3 (McHenry et al, 1998;Li et al, 2003;Zenz et al, 2003;Zhang et al, 2003;Uda et al, 2004;Thumkeo et al, 2005;Takatori et al, 2008;Yu et al, 2008;Naoe et al, 2010). While how these factors are organized into a morphogenetic network for eyelid closure has not been well understood, molecular analyses of these mice have begun to unveil that some of the factors are organized into concerted signal transduction cascades.…”

Section: Map3k1 In Ocular Surface Developmentmentioning

confidence: 99%

c-Jun, at the crossroad of the signaling network

2011

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“…Although in early development, cFoxL2 seems to play a role in the activation and maintenance of aromatase expression, its function in adult ovaries needs to be elucidated. Recent studies on FoxL2 null mice demonstrated that FoxL2 is crucial for primordial follicle formation (Uda et al, 2004;Schmidt et al, 2004). The presence of cFoxL2 expression in the pregranulosa cells of primordial follicles at D14 suggests that cFoxL2 may have similar role in the chicken ovary.…”

Section: Foxl2 and Later Developmentmentioning

confidence: 99%

Isolation of chicken homolog of the FOXL2 gene and comparison of its expression patterns with those of aromatase during ovarian development

Govoroun

Pannetier

Pailhoux

et al. 2004

Developmental Dynamics

192

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Mutations in the forkhead transcription factor gene FOXL2 are involved in ovarian failure, which occurs in human BPES syndrome. This syndrome presents a sexually dimorphic expression, specific to the ovary in several vertebrates. We cloned the open reading frame of chicken FOXL2 (cFoxL2) and studied cFoxL2 expression in developing gonads and during adulthood to examine the role of FOXL2 in ovarian differentiation and function in birds. The spatial and temporal dynamics of cFoxL2 and aromatase expression were analyzed in parallel by using real-time quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry in attempt to investigate the possible role of cFoxL2 in the regulation of aromatase. The expression patterns of cFoxL2 and aromatase transcripts were highly correlated during the sex-differentiation period (4.7-12.7 days of incubation). Aromatase and cFoxL2 proteins were colocalized in the medullar part of female gonads on embryonic day 14. Fourteen days after hatching, cFoxL2 protein was mainly detected in granulosa cells of developing follicles. In adult ovary follicular envelopes, apart from granulosa cells, cFoxL2 transcript and protein were detected at lower levels in theca cells where aromatase was present. A high level of cFoxL2 transcription was also observed in maturing and ovulated oocytes. Our results confirm that FoxL2 is an early regulator of ovarian development in birds and may be involved in aromatase transcription regulation. Developmental Dynamics 231:859 -870, 2004.

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Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development

Cited by 483 publications

References 32 publications

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

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

c-Jun, at the crossroad of the signaling network

Isolation of chicken homolog of the FOXL2 gene and comparison of its expression patterns with those of aromatase during ovarian development

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