Journal Article

The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles

Bérénice A. Benayoun, Sandrine Caburet, Aurélie Dipietromaria, Marc Bailly-Bechet, Frank Batista, Marc Fellous, Daniel Vaiman and Reiner A. Veitia

in Human Molecular Genetics

Volume 17, issue 20, pages 3118-3127
Published in print October 2008 | ISSN: 0964-6906
Published online July 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn209
The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles

Show Summary Details

Preview

The Forkhead transcription factor FOXL2 plays a crucial role in ovarian development and maintenance. In humans, its mutations lead to craniofacial abnormalities, isolated or associated with ovarian dysfunction. Using a combinatorial approach, we identified and characterized a FoxL2 response element (FLRE) and showed that it is highly specific and that it diverges from that of other Forkhead transcription factors. This specificity should prevent aberrant regulation of FOXL2 targets by other members of the family and should prevent ectopic activation of the ovarian differentiation program in testes. We provide evidence that the FLRE is used in naturally occurring promoters. We show that polyAlanine expansions of FOXL2, which are the most frequent pathogenic mutations, induce a length-dependent loss of response on different artificial promoter reporters depending on the number and sequence of the FLREs that they contain. Thus, we provide clear mechanistic evidence explaining how the architecture of promoters influences their sensitivity to decreased transcription factor availability. Furthermore, we speculate that the generally absent ovarian phenotype of patients carrying the most frequent polyAlanine expansion should come from its ability to properly regulate high-affinity ovarian targets. The existence of critical high-affinity ovarian targets would be compatible with the role of FOXL2 in reproduction and ensure developmental and functional robustness. Taken together, our results give mechanistic insights on the molecular pathogenesis of FOXL2 polyAlanine expansions.

Journal Article.  6107 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.