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

Science. 2020 Jun 5;368(6495):1132-1135. doi: 10.1126/science.aay5134.

Daiji Kiyozumi ¹ ², Taichi Noda ¹ ², Ryo Yamaguchi ² ³, Tomohiro Tobita ² ⁴, Takafumi Matsumura ² ³, Kentaro Shimada ² ³, Mayo Kodani ² ³, Takashi Kohda ⁵, Yoshitaka Fujihara ¹ ², Manabu Ozawa ⁶, Zhifeng Yu ⁷, Gabriella Miklossy ⁷, Kurt M Bohren ⁷, Masato Horie ⁸, Masaru Okabe ¹ ² ³, Martin M Matzuk ⁹ ¹⁰ ¹¹ ¹², Masahito Ikawa ¹³ ² ³ ⁴ ⁶

Affiliations

1 Immunology Frontier Research Center, Osaka University, Suita, Osaka 5650871, Japan.
2 Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 5650871, Japan.
3 Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 5650871, Japan.
4 Graduate School of Medicine, Osaka University, Suita, Osaka 5650871, Japan.
5 Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Yamanashi 4008510, Japan.
6 The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 1088639, Japan.
7 Center for Drug Discovery and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
8 Department of CNS Research, Otsuka Pharmaceutical, Kawauchi-cho, Tokushima 771-0192, Japan.
9 Center for Drug Discovery and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mmatzuk@bcm.edu ikawa@biken.osaka-u.ac.jp.
10 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
11 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
12 Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.
13 Immunology Frontier Research Center, Osaka University, Suita, Osaka 5650871, Japan. mmatzuk@bcm.edu ikawa@biken.osaka-u.ac.jp.

PMID: 32499443 DOI: 10.1126/science.aay5134

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.

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