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

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism
  • Animals
  • Cell Communication / genetics
  • Cell Communication / physiology*
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Epididymis / metabolism*
  • Fertility*
  • Infertility, Male / genetics
  • Infertility, Male / metabolism*
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Spermatozoa / metabolism*
  • Testis / metabolism*


  • Membrane Glycoproteins
  • Nell2 protein, mouse
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • Ros1 protein, mouse
  • Endopeptidases
  • ovochymase
  • ADAM Proteins
  • Adam3 protein, mouse
  • Adam32 protein, mouse