Abstract
In most of mammalian embryos, gonadal sex differentiation occurs inside the maternal uterus before birth. In several fetal ovarian grafting experiments using male host mice, an experimental switch from the maternal intrauterine to male-host environment gradually induces partial masculinization of the grafted ovaries even under the wild-type genotype. However, either host-derived factors causing or molecular basis underlying this masculinization of the fetal ovaries are not clear. Here, we demonstrate that ectopic appearance of SOX9-positive Sertoli cell-like cells in grafted ovaries was mediated by the testosterone derived from the male host. Neither Sox8 nor Amh activity in the ovarian tissues is essential for such ectopic appearance of SOX9-positive cells. The transcriptome analyses of the grafted ovaries during this masculinization process showed early downregulation of pro-ovarian genes such as Irx3, Nr0b1/Dax1, Emx2, and Fez1/Lzts1 by days 7–10 post-transplantation, and subsequent upregulation of several pro-testis genes, such as Bhlhe40, Egr1/2, Nr4a2, and Zc3h12c by day 20, leading to a partial sex reversal with altered expression profiles in one-third of the total numbers of the sex-dimorphic pre-granulosa and Sertoli cell-specific genes at 12.5 dpc. Our data imply that the paternal testosterone exposure is partially responsible for the sex-reversal expression profiles of certain pro-ovarian and pro-testis genes in the fetal ovaries in a temporally dependent manner.
Highlights
In mouse sex differentiation, both testicular Sertoli cells and ovarian granulosa cells develop from common supporting cell precursors in the genital ridges [1,2]
Characterization of partial masculinization in embryonic ovaries grafted into male nude mice structures with SOX9-positive Sertoli-like cells appear in the gonadal parenchyma on day15– 20 post-transplantation [17,35]
In ovarian transplants grafted into XX-host, the primary and secondary AMHpositive follicles were well-developed by day 10 post-transplantation, some degenerating follicles with either atretic oocytes or disorganized granulosa cells were present (Fig 1A)
Summary
Both testicular Sertoli cells and ovarian granulosa cells develop from common supporting cell precursors in the genital ridges [1,2]. In XY male mice, SRY, sex-determining region on Y chromosome, directly upregulates an autosomal SRY-related HMG box (Sox) gene, Sox, in bipotential supporting cells from 11.0 days post-coitum (dpc) [3,4,5,6,7]. SOX9 subsequently induces the Sox expression [8,9], in addition to activating several. Characterization of partial masculinization in embryonic ovaries grafted into male nude mice. KAKENHI-PROJECT-14J09465/) (Grant-in-Aid for JSPS Fellows) to KM
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