Hiramatsu Ryuji, Matoba Shogo, Kanai-Azuma Masami, Tsunekawa Naoki, Katoh-Fukui Yuko, Kurohmaru Masamichi, Morohashi Ken-Ichirou, Wilhelm Dagmar, Koopman Peter, Kanai Yoshiakira
Department of Veterinary Anatomy, The University of Tokyo, Yayoi 1-1-1, Bunkyoku, Tokyo 113-8657, Japan.
Development. 2009 Jan;136(1):129-38. doi: 10.1242/dev.029587. Epub 2008 Nov 26.
In mammals, the Y-linked sex-determining gene Sry cell-autonomously promotes Sertoli cell differentiation from bipotential supporting cell precursors through SRY-box containing gene 9 (Sox9), leading to testis formation. Without Sry action, the supporting cells differentiate into granulosa cells, resulting in ovarian development. However, how Sry acts spatiotemporally to switch supporting cells from the female to the male pathway is poorly understood. We created a novel transgenic mouse line bearing an inducible Sry transgene under the control of the Hsp70.3 promoter. Analysis of these mice demonstrated that the ability of Sry to induce testis development is limited to approximately 11.0-11.25 dpc, corresponding to a time window of only 6 hours after the normal onset of Sry expression in XY gonads. If Sry was activated after 11.3 dpc, Sox9 activation was not maintained, resulting in ovarian development. This time window is delimited by the ability to engage the high-FGF9/low-WNT4 signaling states required for Sertoli cell establishment and cord organization. Our results indicate the overarching importance of Sry action in the initial 6-hour phase for the female-to-male switching of FGF9/WNT4 signaling patterns.
在哺乳动物中，Y 连锁的性别决定基因 Sry 通过含 SRY 盒基因 9（Sox9）自主地促进支持细胞前体向睾丸支持细胞分化，从而导致睾丸形成。若没有 Sry 的作用，支持细胞则分化为颗粒细胞，进而导致卵巢发育。然而，Sry 如何在时空上发挥作用，将支持细胞从雌性发育途径转变为雄性发育途径，目前仍知之甚少。我们构建了一种新型转基因小鼠品系，该品系携带一个受 Hsp70.3 启动子控制的可诱导 Sry 转基因。对这些小鼠的分析表明，Sry 诱导睾丸发育的能力仅限于大约胚胎第 11.0 - 11.25 天，这对应于 XY 性腺中 Sry 正常表达开始后的仅 6 小时时间窗口。如果 Sry 在胚胎第 11.3 天之后被激活，Sox9 的激活就无法维持，从而导致卵巢发育。这个时间窗口由参与支持细胞建立和索状组织所需的高 FGF9/低 WNT4 信号状态的能力所界定。我们的结果表明，Sry 在最初 6 小时阶段的作用对于 FGF9/WNT4 信号模式从雌性向雄性的转换至关重要。
