日本大阪大学Masahito Ikawa和美国贝勒医学院Martin M. Matzuk团队合作，揭示了雄性生育能力需要通过OVCH2介导的NELL2 lumicrine信号通路。2020年6月5日，《科学》发表了这一成果。

研究人员证明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因子2（NELL2），能够与孤儿受体酪氨酸激酶c-ros癌基因1（ROS1）特异性结合并介导附睾初始节段（IS）的分化。Nell2缺失的雄性小鼠不育。 IS特异性的分泌蛋白酶卵磷脂酶2（OVCH2）以及A整联蛋白和金属肽酶28（ADAM28）在IS成熟时表达，而OVCH2是精子表面蛋白ADAM3加工所必需的，这是精子受精能力不可缺少的。

该工作揭示了睾丸-表皮-精子（NELL2-ROS1-OVCH2-ADAM3）信号传导通路和男性生育所必需的 lumicrine系统。

据了解， lumicrine系统是一种假定的信号系统，其中睾丸来源的（上游）分泌因子进入男性生殖道，以调节精子成熟所需的附睾（下游）途径。到目前为止，还没有鉴别出 lumicrine因子。

附：英文原文

Title: NELL2-mediated lumicrine signaling through OVCH2 is required for male fertility

Author: Daiji Kiyozumi, Taichi Noda, Ryo Yamaguchi, Tomohiro Tobita, Takafumi Matsumura, Kentaro Shimada, Mayo Kodani, Takashi Kohda, Yoshitaka Fujihara, Manabu Ozawa, Zhifeng Yu, Gabriella Miklossy, Kurt M. Bohren, Masato Horie, Masaru Okabe, Martin M. Matzuk, Masahito Ikawa

Issue&Volume: 2020/06/05

Abstract: 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 Nell2 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.

DOI: 10.1126/science.aay5134

Source: https://science.sciencemag.org/content/368/6495/1132