Anatomical and Molecular Analyses of XY Ovaries from the African Pygmy Mouse <b><i>Mus minutoides</i></b>

Abstract

The African pygmy mouse Mus minutoides is characterized by the presence of a high proportion of fertile XY females in natural populations. This species displays 2 morphologically different X chromosomes: the ancestral X and a shorter one designated as X*, feminizing the X*Y individuals. This strongly suggests that in the presence of an X* chromosome, the male differentiation program is not activated despite a functional Y chromosome. In this study, we compared the histology of the adult ovaries of the 3 female genotypes (XX, XX* and X*Y) and investigated the expression of some of the main genes involved in male and female differentiation. We found that X*Y gonads display a typical ovarian structure without any testicular organization. Moreover, the ovarian somatic marker FOXL2 is detected in X*Y follicle cells and exhibits the same pattern as in XX and XX* ovaries, whereas SOX9 and DMRT1 are absent at all stages of follicular differentiation. However, surprisingly, X*Y ovaries display a higher level of Sry transcripts compared to testes. Our findings confirm the complete sex reversal in X*Y individuals with no apparent sign of masculinization, providing an attractive model to unravel new gene interactions involved in the mammalian sex determination system.

Masculinised Behaviour of XY Females in a Mammal with Naturally Occurring Sex Reversal

“…During the last decade, there has been a growing interest in the ”direct” role of the expression of sex chromosome genes on the shaping of sexual dimorphic behaviours 7 , as opposed to the “indirect” way: trough the action of gonadal hormones 53 . In the African pygmy mouse, the lack of noticeable differences between the anatomy and ovaries of XX, XX* and X*Y females 23 could imply that all female have similar levels of circulating gonadal hormones (though this would have to be confirmed by hormonal assay). So the differences found in this study in terms of aggressiveness, anxiogenous response to novelty and exploratory behaviour is likely to result from the direct influence of genes of the Y, X and X* chromosomes on the brain.…”

“…These genes, and others of the non-recombining region of the Y, could be responsible for differences in anxiogenic response to novelty, locomotor activity and number of aggressions which dissociate Y chromosome bearers (X*Y and XY) from non-bearers (XX and XX*) in the pygmy mouse. Sry is a serious candidate, as it has been shown to be strongly expressed in the brain of X*Y females in the pygmy mouse 23 . In regard to attack latency, X*Y female differ from the XX, and XX* are intermediate, evoking an influence of the X*.…”

“…So while all males are XY, there are three types of females with different sex chromosome complements: XX, XX* and X*Y 20 ; Sex determination is polygenic in this species 22 . The three types of females cannot be told apart phenotypically, they have a similar body mass and ano-genital distance, and all harbour typical ovarian structure 23 , which suggest similar levels of circulating hormones. However, their reproductive performances differ: unexpectedly, X*Y females produce significantly more offspring than the XX and XX* females despite the meiotic issues expected in heterogametic oocytes and the loss of unviable YY embryos.…”

X inactivation in a mammal species with three sex chromosomes

“…Although limited investigation seemed to suggest random X inactivation of either the X or X* in XX* females (H. Winking, personal communication, in Schempp et al (1985)), other results showed more striking patterns, with complete nonrandom X or X* inactivation (100%) in specimens with numerically aberrant X*XY sex chromosome constitution (Schempp et al 1985). Recently, a novel case of unusual mammalian sex determination system was described in the African pygmy mouse, Mus minutoides, a close relative of the house mouse (Veyrunes et al 2010;Rahmoun et al 2014;Zhao et al 2017). In wild populations, up to 75% of females carry a Y chromosome and a peculiar feminizing X* chromosome and are fully fertile.…”

Reduced Activity of SRY and its Target Enhancer Sox9-TESCO in a Mouse Species with X*Y Sex Reversal

“…An atypical sex determination system has been described in the African pygmy mouse Mus minutoides . In this species, regular XX females and XY males exist, but in addition, individuals bearing a normal Y and a variant X (X*) develop as females, despite the presence of the Y chromosome and Sry 12 13 . While the genetic variation that allows the X* to override the male sex-determining programme has not been identified, the other side of the coin is the question of whether the male sex-determining pathway has been weakened in this species, perhaps rendering it vulnerable to be overridden by X*.…”