Department of Pediatrics and Developmental Biology, Tokyo Medical Dental University, Tokyo 113-8510, Japan.
Department of Pediatrics and Developmental Biology, Tokyo Medical Dental University, Tokyo 113-8510, Japan
J Cell Sci. 2019 Apr 15;132(8):jcs223768. doi: 10.1242/jcs.223768.
The nuclear receptor NR5A1 is equally expressed and required for development of the gonadal primordia of both sexes, but, after sex determination, it is upregulated in XY testes and downregulated in XX ovaries. We have recently demonstrated, in mice, that this downregulation is mediated by forkhead box L2 (FOXL2) and hypothesized that adequate suppression of is essential for normal ovarian development. Further, analysis of human patients with disorders/differences of sex development suggests that overexpression of can result in XX (ovo)testicular development. Here, we tested the role of by overexpression in fetal gonads using a -BAC (bacterial artificial chromosome) transgene system. Enforced expression compromised ovarian development in 46,XX mice, resulting in late-onset infertility, but did not induce (ovo)testis differentiation. The phenotype was similar to that of XX mice lacking Notch signaling. The expression level of was significantly reduced in transgenic mice, and the ovarian phenotype was almost completely rescued by treatment with a NOTCH2 agonist. We conclude that suppression of during the fetal period optimizes ovarian development by fine-tuning Notch signaling.
核受体 NR5A1 在两性性腺原基的发育中表达水平相当，且均有其作用，但在性别决定后，它在 XY 睾丸中上调，在 XX 卵巢中下调。我们最近在小鼠中证明，这种下调是由叉头框 L2 (FOXL2) 介导的，并假设 的充分抑制对于正常卵巢发育是必要的。此外，对患有性别发育障碍/差异的人类患者的分析表明， 的过表达可导致 XX（卵睾）发育。在这里，我们使用 -BAC（细菌人工染色体）转基因系统在胎儿性腺中过表达来测试 的作用。强制 表达在 46,XX 小鼠中损害了卵巢发育，导致迟发性不孕，但没有诱导（卵睾）分化。表型与缺乏 Notch 信号的 XX 小鼠相似。转基因小鼠中 的表达水平显著降低，用 NOTCH2 激动剂处理可使卵巢表型几乎完全恢复。我们得出结论，在胎儿期抑制 可通过微调 Notch 信号来优化卵巢发育。
