Immunology Frontier Research Center, Osaka University, Suita, Osaka 5650871, Japan.
Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 5650871, Japan.
Science. 2020 Jun 5;368(6495):1132-1135. doi: 10.1126/science.aay5134.
The lumicrine system is a postulated signaling system in which testis-derived (upstream) secreted factors enter the male reproductive tract to regulate epididymal (downstream) pathways required for sperm maturation. Until now, no lumicrine factors have been identified. We demonstrate that a testicular germ-cell-secreted epidermal growth factor-like protein, neural epidermal growth factor-like-like 2 (NELL2), specifically binds to an orphan receptor tyrosine kinase, c-ros oncogene 1 (ROS1), and mediates the differentiation of the initial segment (IS) of the caput epididymis. Male mice in which had been knocked out were infertile. The IS-specific secreted proteases, ovochymase 2 (OVCH2) and A disintegrin and metallopeptidase 28 (ADAM28), were expressed upon IS maturation, and OVCH2 was required for processing of the sperm surface protein ADAM3, which is required for sperm fertilizing ability. This work identifies a lumicrine system essential for testis-epididymis-spermatozoa (NELL2-ROS1-OVCH2-ADAM3) signaling and male fertility.
亮氨酸系统是一个假定的信号系统，其中睾丸衍生（上游）分泌因子进入雄性生殖道，以调节精子成熟所需的附睾（下游）途径。到目前为止，还没有发现亮氨酸因子。我们证明，一种睾丸生殖细胞分泌的表皮生长因子样蛋白，神经表皮生长因子样蛋白 2（NELL2），特异性结合到一个孤儿受体酪氨酸激酶，c-ros 原癌基因 1（ROS1），并介导附睾头的起始段（IS）的分化。基因敲除的雄性小鼠不育。IS 特异性分泌的蛋白酶，卵黄质酶 2（OVCH2）和 A 型分解素金属蛋白酶 28（ADAM28），在 IS 成熟时表达，OVCH2 是处理精子表面蛋白 ADAM3 的必需条件，ADAM3 是精子受精能力所必需的。这项工作鉴定了一个亮氨酸系统，对于睾丸-附睾-精子（NELL2-ROS1-OVCH2-ADAM3）信号和男性生育能力是必不可少的。
