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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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No annotation is available in this section for this article. The content below is taken from a related TF, FOXL2 (Homo sapiens).

FOXL2 is a member of the superfamily of Forkhead box transcription factors, whose mutations are responsible for the Blepharophimosis Ptosis Epicanthus-inversus Syndrome in humans[1]. This rare genetic disorder is characterized by mild craniofacial defects, which can be isolated (BPES type I) or in association with premature ovarian failure (BPES type II) [2]. No clear genotype-phenotype relationship has been found between mutations and BPES type a priori, but a recent study suggests that mutations leading to BPES type I or II behave differently in functional reporter assays [3]. The BPES phenotype is nicely explained by the defects observed in the two different Foxl2 knock-out mice models, though the invalidation models present a mostly unexplained high perinatal lethality [4][5]. FOXL2 is one of the earliest markers of ovarian determination, and its expression is maintained in ovarian granulosa cells from ovarian determination on, throughout female fertile life in Vertebrates [6]. A recent transcriptomic study in a granulosa cell model has suggested the involvement of FOXL2 in the regulation of cholesterol homeostasis, steroid metabolism, apoptosis, reactive oxygen species detoxification and inflammation/ovulation processes [7]. FOXL2 involvement in the cellular response to oxidative stress has been confirmed and studied more in-depth [8]. All of these processes are not equally affected by FOXL2 naturally-occurring BPES-causing mutations [9][8]. Interestingly, FOXL2 is a highly post-translationnally modified protein, modified by at least phosphorylation, acetylation as well as SUMOylation, and its target gene specificity may be fine-tuned in response to various signals, including cellular stress and sirtuin activation, by the induction of differential post-translational modification isoforms [10][8]. Interestingly, the specific FOXL2 response element (FLRE) is slightly divergent from other Forkheads’, which is compatible with its unique role in gonad primordium determination towards ovarian development [11]. Although FOXL2 expression pattern has not been extensively characterized, FOXL2 has also been involved in the organogenesis and function of the pituitary, where it is expressed mainly in thyreotrope and gonadotrope cells. Its described targets in this organ are mainly involved in the regulation of gonatrophins secretion (transcriptional regulation of the GnRH receptor [12], of the alpha-Glycoprotein Hormone Subunit (alpha-GSU)[13], of the beta subunit of FSH[14] and of Follistatin[15]. To regulate GnRHR and Follistatin expression, FOXL2 has been shown to cooperate by direct binding with Smad3, a downstream effector transcription factor under the regulation of the TGF-beta cytostatic pathway [15][13]. Interestnigly, two recent studies have suggested a potential role for FOXL2 in the regulation of ovarian granulosa cell tumorigenesis: indeed, the first study found its expression was either lost or reduced in the most aggressive cases, and the second study identified a recurring somatic mutation in over 97% of the tumors [16][17]. The molecular pathways explaining FOXL2 involvement in this process will have to be uncovered.

  1. Crisponi L et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat. Genet., 27(2):159-66. (PMID 11175783)
  2. Zlotogora J et al. The blepharophimosis, ptosis, and epicanthus inversus syndrome: delineation of two types. Am. J. Hum. Genet., 35(5):1020-7. (PMID 6613996)
  3. Dipietromaria A et al. Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems. Hum. Mol. Genet., 18(17):3324-33. (PMID 19515849)
  4. Uda M et al. Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum. Mol. Genet., 13(11):1171-81. (PMID 15056605)
  5. Schmidt D et al. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development, 131(4):933-42. (PMID 14736745)
  6. Cocquet J et al. Evolution and expression of FOXL2. J. Med. Genet., 39(12):916-21. (PMID 12471206)
  7. Batista F et al. Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics. Proc. Natl. Acad. Sci. U.S.A., 104(9):3330-5. (PMID 17360647)
  8. Benayoun BA et al. Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations. Hum. Mol. Genet., 18(4):632-44. (PMID 19010791)
  9. Moumné L et al. Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development. Hum. Mol. Genet., 17(7):1010-9. (PMID 18158309)
  1. Benayoun BA et al. The post-translational modification profile of the forkhead transcription factor FOXL2 suggests the existence of parallel processive/concerted modification pathways. Proteomics, 8(15):3118-23. (PMID 18604817)
  2. Benayoun BA et al. The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles. Hum. Mol. Genet., 17(20):3118-27. (PMID 18635577)
  3. Ellsworth BS et al. 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. Mol. Cell. Endocrinol., 206(1-2):93-111. (PMID 12943993)
  4. Ellsworth BS et al. FOXL2 in the pituitary: molecular, genetic, and developmental analysis. Mol. Endocrinol., 20(11):2796-805. (PMID 16840539)
  5. Lamba P et al. A novel role for the forkhead transcription factor FOXL2 in activin A-regulated follicle-stimulating hormone beta subunit transcription. Mol. Endocrinol. (PMID 19324968)
  6. Blount AL et al. FoxL2 and Smad3 Coordinately Regulate Follistatin Gene Transcription. J. Biol. Chem., 284(12):7631-45. (PMID 19106105)
  7. Shah SP et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N. Engl. J. Med., 360(26):2719-29. (PMID 19516027)
  8. Kalfa N et al. Extinction of FOXL2 expression in aggressive ovarian granulosa cell tumors in children. Fertil. Steril., 87(4):896-901. (PMID 17430735)
No annotation is available in this section for this article. The content below is taken from a related TF, FOXL2 (Homo sapiens).
FIGURE 1 FOXL2, a master regulator of the hypothalamus-pituitary-ovarian axis in females
Red text/arrows indicate genes activated by FOXL2 (including itselff). Green text/arrows indicates inhibition by FOXL2, directly or indiretly (the green arrow from SIRT1 to FOXL2 indicates the indirect negative feeback regulation that FOXL2 exerts on itself through activation of SIRT1). Black text indicates indirect regulation or no regulation. The three crucial compartment for reproduction in females are shown in boxes: the hypothalamus, which controls gonadotropin secretion through pulsatile production of GnRH, the anterior pituitary, which contains the FOXL2-expressing thyreotrope and gonadotropes cells and regulates folliculogenesis and ovulation through LH and FSH secretion, and the ovary, the female reproductive organ, which, in turn, regulates GnRH secretion by the hypothalamus via the production of Estrogens (E2) by the CYP19A1 aromatase enzyme (activation or inhibition according to the time of the menstrual cycle). Oxidative stress, which is figured here by the 'activating' yellow lightening, has been shown to enhance FOXL2 transactivation capacity on stress response genes in granulosa ovarian cells. This scheme recapitulates FOXL2 key position in the hypothalamus-pituitary-ovay axis. GnRH: Gonadotropin Releasing Hormone, GnRHR: GNRH Receptor, LH: Luteinizing Hormone, FSH: Folliculo-Stimulating Hormone, FST: follistatin, TSH: Thyroid Stimulating Hormone, MnSOD: mitochondrial Manganese Superoxide Dismutase, IL: interleukin, AMH: Anti-Müllerian Hormone, STAR: Steroidogenic Acute Regulatory gene, E2: estrogens.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.