The gonadotropin releasing hormone (GnRH) receptor activating sequence (GRAS) is a composite regulatory element that interacts with multiple classes of transcription factors including Smads, AP-1 and a forkhead DNA binding protein

Ellsworth, Buffy S.; Burns, Ann T.; Escudero, Kenneth; Duval, Dawn L.; Nelson, Scott E.; Clay, Colin M.

doi:10.1016/s0303-7207(03)00235-1

Cited by 122 publications

(113 citation statements)

References 65 publications

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“…The double immunolocalization of cFoxL2 and aromatase proteins to the sections of the left female gonad at E14 in our study demonstrated that cFoxL2 and aromatase proteins are expressed in the same cells. We performed the search in the chicken aromatase promoter region and upstream sequences for the FoxL2-binding site 5ЈCACAACA 3Ј, previously described in GRAS element (Gonadotropin Releasing hormone receptor Activating Sequence; Ellsworth et al, 2003). We found the site homologous to GRAS at the positions Ϫ668 and Ϫ3453 on the antisense strand and at the position Ϫ3642 on the sense strand.…”

Section: Foxl2 and Ovarian Differentiation In Chickenmentioning

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

119

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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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Section: Foxl2 and Ovarian Differentiation In Chickenmentioning

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

119

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“…31 In the ovary, these include a number of genes fundamental to granulosa cell function and the development of ovarian follicles, including growth differentiation factor 9 (GDF9), inhibin bA (INHBA) and MIS. 32 The regulation of gene expression by FOXL2 involves interactions with other transcription factors including nuclear receptors and the SMAD family of transcription factors; 33,34 both have fundamental roles in ovarian biology.…”

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confidence: 99%

The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary

et al. 2010

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Granulosa cell tumors of the ovary represent B5% of malignant ovarian cancers. It has recently been reported that 95-97% of adult granulosa cell tumors carry a unique somatic mutation in the FOXL2 gene. We undertook this study to verify the presence of the FOXL2 Cys134Trp mutation in two geographically independent cohorts of granulosa cell tumors and to examine the expression pattern of FOXL2 in these tumors. A total of 56 tumors with the histological diagnosis of adult granulosa cell tumor from two centers, Melbourne and Helsinki, were examined for the presence of the mutation using direct sequence analysis. Two granulosa cell tumor-derived cell lines, COV434 and KGN, three juvenile granulosa cell tumors and control tissues were also examined. The expression of the FOXL2 gene was determined using quantitative RT-PCR and/or immunohistochemistry. We found that 52 of the 56 adult granulosa cell tumors harbor the mutation, of which three were hemi/homozygous. Of the four cases with wild-type FOXL2 sequence, reappraisal suggests that three may have been misclassified at primary diagnosis. The KGN cells were heterozygous for the mutation, whereas the COV434 cells had a wildtype FOXL2 genotype. The expression levels of FOXL2 were similar across the adult granulosa cell tumors and the normal ovary controls; one mutation-negative granulosa cell tumor had high FOXL2 mRNA levels, whereas the COV434 cells and two of the three juvenile granulosa cell tumors lacked the expression of FOXL2. Our data provide confirmation of the frequent presence of the FOXL2 C134W mutation in adult granulosa cell tumors and demonstrate that the mutation is not associated with altered FOXL2 expression. The mutation analysis may be a useful tool to differentiate particularly between cell-rich diffuse granulosa cell tumors and mitotically active sex cord-stromal tumors. This unique FOXL2 mutation appears to be characteristic of adult granulosa cell tumors.

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“…Only three of them, namely the genes encoding the gonadotropin-releasing hormone receptor (GnRHr), the alpha subunit of the gonadotropins (Cga), and the steroidogenic acute regulatory protein (StAR) have been reported so far (11)(12)(13). We have recently suggested that the aromatase gene (CYP19A1) is transcriptionally activated by FOXL2 (14,15).…”

mentioning

confidence: 99%

Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics

Batista

Vaiman

Dausset

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

110

102

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FOXL2 is a gene encoding a forkhead transcription factor, whose mutations are responsible for the blepharophimosis-ptosisepicanthus inversus syndrome that often involves premature ovarian failure. FOXL2 is one of the earliest ovarian markers and it offers, along with its targets, an excellent model to study ovarian development and function in normal and pathological conditions. We have recently shown that the aromatase gene is a target of FOXL2, and only three other targets have been reported so far. To detect potential transcriptional targets of FOXL2, we used DNA chips and quantitative PCR to compare the transcriptomes of granulosa-like cells overexpressing, or not, FOXL2. This analysis showed that mediators of inflammation, apoptotic and transcriptional regulators, genes involved in cholesterol metabolism, and genes encoding enzymes and transcription factors involved in reactive oxygen species detoxification were up-regulated. On the other hand, FOXL2 down-regulated the transcription of several genes involved in proteolysis and signal transduction and in transcription regulation. A bioinformatic analysis was conducted to discriminate between potential target promoters activated and repressed by FOXL2. In addition, the promoters of strongly activated genes were enriched in forkhead recognition sites, suggesting that these genes might be direct FOXL2 targets. Altogether, these results provide insight into the activity of FOXL2 and may help in understanding the mechanisms of pathogenesis of FOXL2 mutations if the targets prove to be the same in the ovary.forkhead ͉ infertility ͉ premature ovarian failure ͉ ovary

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The gonadotropin releasing hormone (GnRH) receptor activating sequence (GRAS) is a composite regulatory element that interacts with multiple classes of transcription factors including Smads, AP-1 and a forkhead DNA binding protein

Cited by 122 publications

References 65 publications

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

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

The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary

Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics

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