FOXL2 activates P450 aromatase gene transcription: towards a better characterization of the early steps of mammalian ovarian development

Abstract

Previous studies have equated FOXL2 as a crucial actor in the ovarian differentiation process in different vertebrate species. Its transcriptional extinction in the polled intersex syndrome (PIS) leads primarily to a drastic decrease of aromatase (CYP19) expression in the first steps of goat ovarian development. In this study, we provide a better characterization of early ovarian development in goat, and we provide experimental evidence demonstrating that FOXL2 represents a direct transcriptional activator of the CYP19 gene through its ovarian-specific promoter 2. Moreover, the ovarian location of FOXL2 and CYP19 proteins, together with their expression profiles in the female gonads, stress the involvement of FOXL2 co-factor(s) for regulating CYP19 transcription. Expressional analyses show that activin-A can be considered as a strong candidate for being one of these FOXL2 co-factors. Finally, we discuss evidence for a role of activin and estrogens in somatic and germinal cell proliferation occurring before germ cell meiosis. This period, of 20 days in goat, seems to have no equivalent in mouse. This species-specific difference could explain the phenotype discrepancy observed between XX goat PIS −/− and XX mouse Foxl2 −/− .

A study of goat SRY protein expression suggests putative new roles for this gene in the developing testis of a species with long‐lasting SRY expression

“…Because of the greater sensitivity of gene dosage in nonmouse species, the balance between male and female signals should be maintained throughout life in both sexes. This hypothesis is also in line with the results of cross-species transgenesis experiments showing that goat SRY could act as a mouse testicular determinant; i.e., as a Sox9 up-regulator (Pannetier et al, 2006a), but in fact mouse Sry seems to be incapable of up-regulating the human SOX9 gene in mouse testes (Wunderle et al, 1998).…”

“…In the past, we had studied the expression of SRY (Pannetier et al, 2006a) and SOX9 (Pailhoux et al, 2002) during goat gonad development with RT-PCR in different studies, at several developmental stages and using a nonquantitative PCR approach. Consequently, to obtain a clearer view of crucial gonad gene expression profiles throughout testis development, and particularly before the up-regulation of SOX9, we performed a detailed expression evaluation of five genes during goat testicular differentiation using a quantitative PCR approach on reverse-transcribed RNA (RT-qPCR).…”

“…This is particularly true between mice and other mammals. The mouse SRY protein displays specific structural features, such as a long C-terminal part encompassing a glutamine-rich region and a very short N-terminal part composed of two amino-acids (Tucker and Lundrigan, 1993;Pannetier et al, 2006a). Another important difference between the mouse and other mammals lies in the expression profile of this gene.…”

Characterization of early molecular sex differentiation in rainbow trout, Oncorhynchus mykiss

“…In the mouse, the inactivation of Foxl2 (Ottolenghi et al, 2005), Fst (Jorgez et al, 2004), or Cyp19 (Britt et al, 2002) leads to the development of Sertoli cell tubule-like structures in female gonads. In addition, recent work in the goat (Pannetier et al, 2006) and in the tilapia (Wang et al, 2007) also suggests that Foxl2 may be a direct transcriptional activator of Cyp19. Considering this and the tight positive temporal correlation observed between the expression profiles of cyp19a1, fst, foxl2a, and inha during early ovarian differentiation in trout, a close interaction of these genes for the maintenance of granulosa cell differentiation and/or estrogen production may be hypothesized.…”

FOXL2, le gardien de l’identité ovarienne

“…En effet, dans l'espèce caprine les oestrogè-nes sont produits très tôt dans la gonade femelle, participant à la morphogenèse ovarienne précoce. Cette production hormonale est directement sous le contrôle de FOXL2 qui régule positivement l'expression du gène codant pour l'aromatase (responsable de la conversion des androgènes en oestrogènes) (Figure 1) [14]. Au contraire, dans l'espèce murine, le développement ovarien se fait en l'absence de toute production hormonale et ce n'est qu'après la naissance, lors de la croissance folliculaire, que la stéroïdogenèse ovarienne se met en place.…”