A small secreted protein NICOL regulates lumicrine-mediated sperm maturation and male fertility

Daiji Kiyozumi*, Kentaro Shimada, Michael Chalick, Chihiro Emori, Mayo Kodani, Seiya Oura, Taichi Noda, Tsutomu Endo, Martin M. Matzuk, Daniel H. Wreschner*, Masahito Ikawa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the epididymis. Males lacking Nicol are sterile due to impaired NELL2-mediated lumicrine signalling, leading to defective epididymal differentiation and deficient sperm maturation but can be restored by NICOL expression in testicular germ cells. Our results demonstrate how lumicrine signalling regulates epididymal function for successful sperm maturation and male fertility.

Original languageEnglish
Article number2354
JournalNature Communications
Issue number1
StatePublished - Dec 2023


FundersFunder number
Futaba foundation223074
National Institutes of HealthR01HD088412, P01HD087157
Bill and Melinda Gates FoundationINV-001902
Japan Foundation for Applied Enzymology2022-12
Japan Society for the Promotion of ScienceJP21K19263, JP19H05750, JP21H05033, JP21H00231, JP21H02487
Ministry of Education, Culture, Sports, Science and Technology
Japan Science and Technology AgencyJPMJCR21N1, JPMJPR2143
Osaka University


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