NELL2-mediated lumicrine signaling through OVCH2 is required for male fertility
- 5 June 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 368 (6495), 1132-1135
- https://doi.org/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.Keywords
Funding Information
- Bill and Melinda Gates Foundation (INV-001902)
- Bill and Melinda Gates Foundation (INV-001902)
- Takeda Science Foundation
- Japan Agency for Medical Research and Development (JP19gm5010001)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD088412)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD088412)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD087157)
- Japan Society for the Promotion of Science (18K14612)
- Japan Society for the Promotion of Science (JP17H01394)
- Japan Society for the Promotion of Science (JP25112007)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD087157)
- Japan Society for the Promotion of Science (JP19H05750)
- Japan Society for the Promotion of Science (JP15K06999)
- Japan Society for the Promotion of Science (JP16KK0180)
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