Testicular differentiation occurs in absence of R-spondin1 and Sox9 in mouse sex reversals.
Testicular differentiation occurs in absence of R-spondin1 and Sox9 in mouse sex reversals.
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DOI：
10.1371/journal.pgen.1003170
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Chaboissier MC
中科院分区：
文献类型：
--
作者：
Lavery R;Chassot AA;Pauper E;Gregoire EP;Klopfenstein M;de Rooij DG;Mark M;Schedl A;Ghyselinck NB;Chaboissier MC
在哺乳动物中，雄性性别决定由 SRY 依赖性的 Sox9 激活控制，而雌性发育则涉及 R-spondin1 (RSPO1)，它是 WNT/β-catenin 信号通路的激活剂。对小鼠的遗传分析表明，Sry 和 Sox9 是诱导睾丸发育所必需且充分的。因此，这些基因被认为是雄性途径的主要调节因子。事实上，XX Rspo1 突变小鼠的雌雄性别逆转与 Sox9 表达相关，表明该转录因子在病理条件下诱导睾丸分化。出乎意料的是，我们在这里发现，同时缺乏Rspo1和Sox9的XX突变体（称为XX Rspo1KOSox9cKO）可以发生睾丸分化，这表明Sry和Sox9对于诱导雌性向雄性性逆转来说是可有可无的。分子分析显示 Sox8 和 Sox10 均表达，表明除 Sox9 之外的 Sox 基因的激活可以诱导 Rspo1KOSox9cKO 小鼠的雄性分化。此外，由于睾丸发育发生在 XY Rspo1KOSox9cKO 小鼠中，因此我们的数据表明，Rspo1 是 XY Sox9cKO 小鼠中雄性向雌性逆转的主要效应器。因此，Rspo1 不仅在正常情况下而且在性逆转情况下都是卵巢发育的重要激活剂。综上所述，这些数据表明，男性和女性的性别分化都是由不同的、活跃的遗传途径诱导的。因此，将女性分化视为默认途径的教条需要彻底修改。哺乳动物的性别决定是由 Y 连锁基因 SRY 的父系遗传控制的。使用小鼠模型表明，Sry 的主要（如果不是唯一）作用是激活转录因子 Sox9，而这两个基因对于雄性发育是必要且充分的。事实上，Sry 和/或 Sox9 表达缺陷会导致 XY 个体的性别逆转。在 XX 个体中，Rspo1 对于卵巢发育很重要，XX Rspo1 突变体的雌性向雄性逆转就证明了这一点。由于睾丸分化与 Sox9 表达同时出现，因此假设 Sox9 是 XX Rspo1 突变体中睾丸分化的诱导剂。我们的基因研究表明 i) Sry 和 Sox9 都不是女性向男性性别逆转所必需的； ii) 其他男性化因子如 Sox8 和 Sox10 在性逆转条件下被激活； iii) Rspo1 是 XY Sox9 突变体中男女性别逆转的主要效应子。这些数据共同表明，男性和女性遗传途径都是参与性别决定的主要效应器，并且默认女性途径的长期教条应该明确修改。
In mammals, male sex determination is governed by SRY-dependent activation of Sox9, whereas female development involves R-spondin1 (RSPO1), an activator of the WNT/beta-catenin signaling pathway. Genetic analyses in mice have demonstrated Sry and Sox9 to be both required and sufficient to induce testicular development. These genes are therefore considered as master regulators of the male pathway. Indeed, female-to-male sex reversal in XX Rspo1 mutant mice correlates with Sox9 expression, suggesting that this transcription factor induces testicular differentiation in pathological conditions. Unexpectedly, here we show that testicular differentiation can occur in XX mutants lacking both Rspo1 and Sox9 (referred to as XX Rspo1KOSox9cKO ), indicating that Sry and Sox9 are dispensable to induce female-to-male sex reversal. Molecular analyses show expression of both Sox8 and Sox10, suggesting that activation of Sox genes other than Sox9 can induce male differentiation in Rspo1KOSox9cKO mice. Moreover, since testis development occurs in XY Rspo1KOSox9cKO mice, our data show that Rspo1 is the main effector for male-to-female sex reversal in XY Sox9cKO mice. Thus, Rspo1 is an essential activator of ovarian development not only in normal situations, but also in sex reversal situations. Taken together these data demonstrate that both male and female sex differentiation is induced by distinct, active, genetic pathways. The dogma that considers female differentiation as a default pathway therefore needs to be definitively revised. Mammalian sex determination is controlled by the paternal transmission of the Y-linked gene, SRY. Using mouse models, it has been shown that the main, if not the only, role of Sry is to activate the transcription factor Sox9, and these two genes are necessary and sufficient to allow male development. Indeed, defects in Sry and/or Sox9 expression result in male-to-female sex reversal of XY individuals. In XX individuals, Rspo1 is important for ovarian development as evidenced by female-to-male sex reversal of XX Rspo1 mutants. Since testicular differentiation appears concomitantly with Sox9 expression, it was assumed that Sox9 is the inducer of testicular differentiation in XX Rspo1 mutants. Our genetic study shows that i) neither Sry nor Sox9 are required for female-to-male sex reversals; ii) other masculinizing factors like Sox8 and Sox10 are activated in sex reversal conditions; iii) Rspo1 is the main effector of male-to-female sex reversal in the XY Sox9 mutants. Together these data suggest that male and female genetic pathways are both main effectors involved in sex determination and that the long-standing dogma of a default female pathway should definitively be revised.
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影响因子：
3.5
作者：
Chassot, Anne-Amandine;Ranc, Fariba;Chaboissier, Marie-Christine
通讯作者：
Chaboissier, Marie-Christine
DOI：
10.1073/pnas.0600994103
发表时间：
2006-08-08
影响因子：
11.1
作者：
Gao, Fei;Maiti, Sourindra;Huff, Vicki
通讯作者：
Huff, Vicki
影响因子：
4
作者：
Barrios, Florencia;Filipponi, Doria;Dolci, Susanna
通讯作者：
Dolci, Susanna
影响因子：
64.5
作者：
Arango, NA;Lovell-Badge, R;Behringer, RR
通讯作者：
Behringer, RR
影响因子：
2.3
作者：
Bradford, S. T.;Wilhelm, D.;Koopman, P.
通讯作者：
Koopman, P.