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

Abstract

Foxl2 is a member of the large family of Forkhead Box (Fox) domain transcription factors. It emerged during the last 15 years as a key player in ovarian differentiation and oogenesis in vertebrates and especially mammals. This review focuses on Foxl2 genes in light of recent findings on their evolution, expression, and implication in sex differentiation in animals in general. Homologs of Foxl2 and its paralog Foxl3 are found in all metazoans, but their gene evolution is complex, with multiple gains and losses following successive whole genome duplication events in vertebrates. This review aims to decipher the evolutionary forces that drove Foxl2/3 gene specialization through sub- and neo-functionalization during evolution. Expression data in metazoans suggests that Foxl2/3 progressively acquired a role in both somatic and germ cell gonad differentiation and that a certain degree of sub-functionalization occurred after its duplication in vertebrates. This generated a scenario where Foxl2 is predominantly expressed in ovarian somatic cells and Foxl3 in male germ cells. To support this hypothesis, we provide original results showing that in the pea aphid (insects) foxl2/3 is predominantly expressed in sexual females and showing that in bovine ovaries FOXL2 is specifically expressed in granulosa cells. Overall, current results suggest that Foxl2 and Foxl3 are evolutionarily conserved players involved in somatic and germinal differentiation of gonadal sex.

Genome-wide identification of novel ovarian-predominant miRNAs: new insights from the medaka (Oryzias latipes)

“…While ddx6 (DEAD-box protein-103 / gemin3) is known to regulate the meiosis progression57, ddx20 directly represses the transcriptional activity of the transcription factor foxL2 and the steroidogenic factor SF-1 5859. FoxL2 and SF-1 are both key genes for gonadal differentiation6061. These data are consistent with a possible role of miR-6352 in ovarian development and oocyte formation.…”

Comparison of sex determination mechanism of germ cells between birds and fish: Cloning and expression analyses of chicken forkhead box L3‐like gene

“…The forkhead domain sequence was found to be highly conserved in four different species (Figure 3). [9][10][11] Moreover, construction of a phylogenetic tree revealed that the chicken foxl3like gene belongs to the FOXL3 subset of the FOXL family ( Figure 4). This suggested that the FOXL3 amino acid sequence changed rapidly during vertebrate evolution.…”

Forkhead box transcription factor L2 activates Fcp3C to regulate insect chorion formation

“…FoxL2 is also required to prevent the transdifferentiation of an adult ovary to a testis [17]. In addition to humans and mice, FoxL2 has also been studied in numerous species such as fishes, chickens, frogs and goats [18]. In the pea aphid Acyrthosiphon pisum , RNA-seq data revealed that FoxL2 is predominantly expressed in sexual females [18].…”

“…In addition to humans and mice, FoxL2 has also been studied in numerous species such as fishes, chickens, frogs and goats [18]. In the pea aphid Acyrthosiphon pisum , RNA-seq data revealed that FoxL2 is predominantly expressed in sexual females [18]. In the yellow fever mosquito, Aedes aegypti , the transcript level of FoxL2 in ovaries was elevated after a blood meal.…”