<i>FOXL2 </i>Impairment in Human Disease

Abstract

FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical consequences of FOXL2 impairment in human disease. In line with other forkhead transcription factors, its constitutional genetic defects and a somatic mutation lead to developmental disease and cancer, respectively. More than 100 unique constitutional mutations and regulatory defects have been found in blepharophimosis syndrome (BPES), a complex eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). In agreement with the BPES phenotype, FOXL2 is expressed in the developing eyelids and in fetal and adult ovaries. Two knock-out mice and at least one natural animal model, the Polled Intersex Syndrome goat, are known. They recapitulate the BPES phenotype and have provided many insights into the ovarian pathology. Only a few constitutional mutations have been described in nonsyndromic POF. Moreover, a recurrent somatic mutation p.C134W was found to be specific for adult ovarian granulo-sa cell tumors. Functional studies investigating the consequences of FOXL2 mutations or regulatory defects have shed light on the molecular pathogenesis of the aforementioned conditions, and contributed considerably to genotype-phenotype correlations. Recently, a conditional knock-out of Foxl2 in the mouse induced somatic transdifferentiation of ovary into testis in adult mice, suggesting that Foxl2 has an anti-testis function in the adult ovary. This changed our view on the ovary and testis as terminally differentiated organs in adult mammals. Finally, this might have potential implications for the understanding and treatment of frequent conditions such as POF and polycystic ovary syndrome.

FOXL2: a central transcription factor of the ovary

“…Mutations affecting this gene can be detected in about 90% of BPES patients and in 70% of them, the mutation is intragenic (Crisponi et al 2001, Verdin & De Baere 2012. FOXL2 is a single-exon gene encoding a protein of 376 amino acids.…”

“…FOXL2 is a single-exon gene encoding a protein of 376 amino acids. The protein contains a forkhead DNAbinding domain and a polyalanine tract of 14 residues, which is expanded to 24 residues in 30% of BPES cases with intragenic mutations (Cocquet et al 2003, Verdin & De Baere 2012. FOXL2 is highly conserved among vertebrates, undergoes strong purifying selection (Cocquet et al 2003) and has emerged as a key factor of ovarian biology.…”

Foxl2 and Its Relatives Are Evolutionary Conserved Players in Gonadal Sex Differentiation

“…Among all these genes, Foxl2 has attracted particular attention during the last 15 years as a key player due to its involvement in sex differentiation and oogenesis [Baron et al, 2005;Benayoun et al, 2009;Veitia, 2010;Boulanger et al, 2014;Georges et al, 2014a;Nicol and Yao, 2014]. A substantial amount of information on FOXL2 action was initially acquired from studies in humans and other mammals, and many excellent reviews have already been published, most centered on the roles of FOXL2 in normal or pathological female development in mammals and/or vertebrates [Fuhrer, 2002;Baron et al, 2005;De Baere et al, 2005;Benayoun et al, 2009Benayoun et al, , 2010Beysen et al, 2009;Kobel et al, 2009;Pisarska et al, 2011;Uhlenhaut and Treier, 2011;Biason-Lauber, 2012;Caburet et al, 2012;Verdin and De Baere, 2012;Takahashi et al, 2013;Georges et al, 2014a;Rosario et al, 2014;Leung et al, 2016]. The present review focuses on ' foxl2 ' genes in light of recent findings on their evolution, expression, and roles in sex differentiation in animals.…”

Involvement of FOXL2 and RSPO1 in Ovarian Determination, Development, and Maintenance in Mammals

“…Whatever these differences may be, FOXL2 is a key player in ovarian differentiation, and mutations of this gene impact the function of granulosa cells at various stages of their differentiation, ultimately leading to various ovarian pathologies [Verdin and De Baere 2012]. At the time of sex determination, FOXL2 mutation induces sex reversal in XX goats [Boulanger et al, 2014], folliculogenesis defects in mice [Schmidt et al, 2004;Uda et al, 2004], and type I BPES with POF [Beysen et al, 2008] or non-syndromic POF without BPES in humans [Laissue et al, 2009].…”