Genetics and Genomics of Gonadal Development

Our research focus is ovarian development and function via the molecular analysis of the blepharophimosis syndrome (BPES: blepharophimosis, ptosis, epicantus inversus syndrome).

BPES involves craniofacial malformations associated with premature ovarian failure, and results from mutations in the FOXL2 gene, which encodes a transcription factor. Immunohistochemical analysis with our antibodies showed that FOXL2 protein is expressed in the cell nuclei of peri-occular tissues and in specific ovarian cells (from the onset of gonadal determination until adulthood), in agreement with the BPES phenotype.

We have performed in collaboration the first large-scale FOXL2 mutation search in BPES patients. One third of the mutations are expansions of a polyalanine domain present in FOXL2 (from 14 to 24 residues). Later on, we showed that the polyalanine-expanded protein aggregated in the nucleus and the cytoplasm. This mutant protein would be trapped in the aggregates and would be unable to reach its transcriptional targets. We have recently shown that other types of mutations in FOXL2 lead also to its intracellular aggregation.

To better understand the function of FOXL2 and the pathogenic mechanisms of its mutations, we will exhaustively search its transcriptional targets. A pilot study has already shown that FOXL2 may participate in the regulation of apoptosis, cholesterol metabolism and oxygen free radical detoxification. FOXL2 might well be an ovarian senescence determinant. We have recently shown that oxidative and thermal stress induce an increased expression of FOXL2 in the ovary, associated with a spectacular change in the profile of its post-transcriptional modifications. Therefore, FOXL2 appears to be a key factor in ovarian aging, a process that would be accelerated in the BPES. It is also involved in the etiology of ovarian granulosa cell tumors.

Projects :
1. Study of the role of FOXL2 in the ovary,
2. Understanding of the pathogenic mechanisms of FOXL2 mutations in vivo,
3. Exploration of the genetic network directly regulated by FOXL2, during the early ovarian development and at various stages of follicular maturation by ChIP-on-Chip and transcriptomics,
4. Caracterisation of the various post-transcriptional modifications of FOXL2 and their functional impact, in the developping and adult ovary, by immunoprecipitation and mass spectrometry.
5. Identification of the signalisation pathways that regulate the activity of FOXL2.
6. Undesstand the involvement of FOXL2 in the etiology of ovarian granulosa cell tumors.

Sélection of Publications

Benayoun BA, Veitia RA. A post-translational modification code for transcription factors: sorting through a sea of signals. Trends in Cell Biology. 2009, 19(5):189-97 
Abstract

Benayoun BA, Batista F, Auer J, Dipietromaria A, L'hôte D, De Baere E, Veitia RA. 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. 2009, 18(4):632-44.
Abstract

Benayoun BA, Caburet S, Dipietromaria A, Bailly-Bechet M, Batista F, Fellous M, Vaiman D, Veitia RA. The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles. Hum Mol Genet. 2008 Oct 15;17(20):3118-27.
Abstract

Moumné L, Dipietromaria A, Batista F, Kocer A, Fellous M, Pailhoux E, Veitia RA. 2008. Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development. Hum Mol Genet. 2008 Apr 1;17(7):1010-9.
Abstract

Batista F, Vaiman D, Dausset J, Fellous M, Veitia RA. Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics. Proc Natnl Acad Sci. USA. 2007. 104(9):3330-5.
Abstract

Last modified 03/14/2011

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