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FOXL2, a critical regumator of steroid synthesis, acts as a female sex-determining gene in goats

Abstract : In goats, the PIS (Polled Intersex Syndrome) mutation results in hornlessness of heterozygous (PIS+/-) and homozygous (PIS-/-) animals of both sexes, and to a female-to-male sex-reversal in XX animals homozygous for the mutation (XX PIS-/-). The PIS mutation is a regulatory mutation which corresponds to a 11.7 kb-deletion on goat chromosome 1, inducing a long-range transcriptional effect on FOXL2 and on three non-coding RNAs. For several years, we have accumulated evidences that these ncRNAs are involved in FOXL2 expression regulation, and we have now demonstrated, by using zinc-finger nuclease-directed mutagenesis, that the sole “acting” gene of the PIS locus is FOXL2. Thus, in goats, the transcriptional silencing of FOXL2 in the early-developing XX PIS-/- or FOXL2-/- gonad is responsible for testis formation in a female genetic context. This sex-determining role of FOXL2 seems to be conserved in most of vertebrate species including mammals but it has been lost in mice. In order to clarify the role of FOXL2 in early developing ovaries and to understand the species-specific differences between goats and mice following FOXL2 gene ablation, mRNA profiles have been determined by high-throughput RNA sequencing on early developing XX gonads with (PIS+/+ or PIS+/-) or without (PIS-/-) FOXL2. The RNA-sequencing results confirmed by RT-qPCR, showed that FOXL2 inhibits testicular differentiation on top of being an activator of ovarian development. This inhibition takes place at three levels; first, FOXL2 represses androgens production (also enhancing aromatase and estrogens production), then, it protects XX germ cells fate by inhibiting CYP26b1 expression, and finally it represses Sertoli cells differentiation, by inhibiting the DMRT1 gene that should lead to SOX9 up-regulation. Indeed, our data show that DMRT1 is up-regulated in early XX sex-reversed gonads before SOX9 up-regulation; SOX9 remaining expressed as in normal ovaries at this early differentiating gonadic stage. Altogether our results lead us to propose a model for the early gonadic switch in goats that is different from those demonstrated in mice. The relevance of this model and its conservation across vertebrate species will be discussed.
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https://hal.inrae.fr/hal-02741073
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Submitted on : Wednesday, June 3, 2020 - 12:32:15 AM
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  • HAL Id : hal-02741073, version 1
  • PRODINRA : 271570

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Maëlle Pannetier, Maeva Elzaiat, Laurent Boulanger, Aurelie Allais-Bonnet, Laurence Gall, et al.. FOXL2, a critical regumator of steroid synthesis, acts as a female sex-determining gene in goats. 27. Conference of European Comparative Endocrinologists, European Society of Endocrinology (ESE). GBR., Aug 2014, Rennes, France. ⟨hal-02741073⟩

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