School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
PLoS One. 2020 Dec 30;15(12):e0244553. doi: 10.1371/journal.pone.0244553. eCollection 2020.
Leydig cells represent the steroidogenic lineage of mammalian testis, which produces testosterone. Genetic evidence indicates the requirement of Notch signaling in maintaining a balance between differentiated Leydig cells and their progenitors during fetal development. In primary Leydig cells, Notch1 expression decreases with testicular development, while the expression of its ligand, Jagged1, remains relatively unchanged, suggesting that the roles of Jagged1 extend beyond Notch signaling. In addition, Jagged1 is known to be processed into its intracellular domain, which then translocate to the nucleus. In this study, we investigated the effect of Jagged1 intracellular domain (JICD) on steroidogenesis in Leydig cells. The independent overexpression of JICD in MA-10 Leydig cells was found to inhibit the activity of cAMP-induced Nur77 promoter. In addition, JICD suppressed Nur77 transactivation of the promoter of steroidogenic genes such as P450scc, P450c17, StAR, and 3β-HSD. Further, adenovirus-mediated overexpression of JICD in primary Leydig cells repressed the expression of steroidogenic genes, consequently lowering testosterone production. These results collectively suggest that steroidogenesis in testicular Leydig cells, which is regulated by LH/cAMP signaling, is fine-tuned by Jagged1 during testis development.
间质细胞代表了哺乳动物睾丸的类固醇生成谱系，其产生睾酮。遗传证据表明，在胎儿发育过程中，Notch 信号在维持分化的间质细胞与其祖细胞之间的平衡中是必需的。在原代间质细胞中，Notch1 的表达随着睾丸发育而降低，而其配体 Jagged1 的表达相对不变，这表明 Jagged1 的作用超出了 Notch 信号。此外，Jagged1 已知被加工成其细胞内结构域，然后易位到细胞核。在这项研究中，我们研究了 Jagged1 细胞内结构域 (JICD) 对间质细胞类固醇生成的影响。在 MA-10 间质细胞中独立过表达 JICD 被发现抑制 cAMP 诱导的 Nur77 启动子的活性。此外，JICD 抑制了类固醇生成基因如 P450scc、P450c17、StAR 和 3β-HSD 的启动子的 Nur77 反式激活。此外，腺病毒介导的 JICD 在原代间质细胞中的过表达抑制了类固醇生成基因的表达，从而降低了睾酮的产生。这些结果共同表明，由 LH/cAMP 信号调节的睾丸间质细胞的类固醇生成，在睾丸发育过程中受到 Jagged1 的精细调节。
