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

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.