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

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Science  05 Jun 2020:
Vol. 368, Issue 6495, pp. 1132-1135
DOI: 10.1126/science.aay5134

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Local control of sperm maturation

Newly produced spermatozoa within the testis do not have fertilizing ability but become fully functional when they mature in the epididymis. The development of the epididymis itself is dependent on testicular factors arriving via luminal flow. Improper signaling between the testis and epididymis is hypothesized to result in male infertility. Kiyozumi et al. identified NELL2 as a testicular luminal protein that binds to its receptor, ROS1, on the luminal epididymis surface and induces epididymal differentiation (see the Perspective by Lord and Oatley). In turn, differentiated epididymis secretes a fertility-essential protease, ovochymase-2, to make spermatozoa fully mature and functional. Thus, testis-epididymis interorgan communication by this “lumicrine” regulation ensures mammalian reproduction.

Science, this issue p. 1132; see also p. 1053


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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