Novel switch protein that 'turns on' sperm for fertilization

June 04, 2020

Osaka, Japan and Houston, Texas, USA - For a sperm produced in the testis of a man to fertilize a woman's egg, the sperm must first mature in a man's epididymis. Now, an international team of researchers has identified a chain of events in which a protein secreted by the testis travels in the luminal fluid, binds to a receptor on the epididymis to induce its differentiation and secretion of a second protein that matures the sperm and enables each sperm to be motile in females.

In a new study published in Science, researchers from Osaka University and Baylor College of Medicine have identified NELL2, a secreted protein factor that acts on the epididymis through this novel "lumicrine" pathway to mediate sperm maturation.

Sperm are produced in the seminiferous tubules of the testis and transit through the epididymis, a long, convoluted tube linked to the vas deferens. When the sperm enter the epididymis, they are not motile and are incapable of fertilization; however, in their passage through the epididymis, the sperm are provided an appropriate environment for maturation and storage pending ejaculation.

It has been hypothesized that proteins released by the testis (upstream) could act on the epididymis (downstream); however, until now, the proteins working through this intriguing lumicrine system of signaling have remained elusive. While it was known that the orphan receptor tyrosine kinase ROS1 expressed in the initial segment of the epididymis is necessary for its differentiation, neither the testicular factors that regulate initial segment differentiation nor the process of sperm maturation had been fully understood.

The researchers zeroed in on NELL2, secreted by testicular germ cells, as a putative lumicrine regulator of fertility. "Using innovative genome editing technology, we generated knockout mice lacking the Nell2 gene and showed that these knockout males are sterile due to a defect in sperm motility," explains Daiji Kiyozumi, lead author. "Moreover, their infertility could be rescued with a germ-cell-specific transgene, thus excluding other sites of expression. We also illustrated lumicrine signaling by demonstrating tagged NELL2 in the epididymal lumen."

The research team observed that spermatogenesis proceeds normally in Nell2 knockout mouse testes but their epididymis was poorly differentiated, similar to Ros1 knockout mice. Following mating, neither Nell2 knockout nor Ros1 knockout spermatozoa can enter the uterine tubes or fertilize an egg. Further investigation showed that the Nell2 knockout epididymis is incapable of making a key protease, OVCH2, that processes a sperm surface protein, ADAM3, essential for male fertility.

Elaborating on the significance of these novel studies, Professors Masahito Ikawa and Martin M. Matzuk, senior authors, say, "We discovered a complicated cascade of events in which disruption of any point in this lumicrine pathway causes a male to be infertile. Our findings have important translational implications for diagnostic and therapeutic research in male infertility and male contraceptive development. This unique transluminal communication pathway between tissues and organs likely functions elsewhere in our bodies."
-end-
The article "NELL2-mediated lumicrine signaling through OVCH2 is required for male fertility" is published in Science at DOI: https://doi.org/10.1126/science.aay5134

About Osaka University

Osaka University was founded in 1931 as one of the seven imperial universities of Japan and now has expanded to one of Japan's leading comprehensive universities. The University has now embarked on open research revolution from a position as Japan's most innovative university and among the most innovative institutions in the world according to Reuters 2015 Top 100 Innovative Universities and the Nature Index Innovation 2017. The university's ability to innovate from the stage of fundamental research through the creation of useful technology with economic impact stems from its broad disciplinary spectrum.

Website: https://resou.osaka-u.ac.jp/en/top

About Baylor College of Medicine

Baylor College of Medicine in Houston is recognized as health sciences university and is known for excellence in education, research and patient care. It is the only private medical school in the greater southwest and is ranked 22nd among medical schools for research and 4th for primary care by U.S. News & World Report. Baylor is listed 20th among all U.S. medical schools for National Institutes of Health funding and No. 1 in Texas. The Baylor pediatrics program ranked 8th among all pediatric programs, reflecting the strong affiliation with Texas Children's Hospital where our faculty care for pediatric patients and our students and residents train. Located in the Texas Medical Center, Baylor has affiliations with seven teaching hospitals and jointly owns and operates Baylor St. Luke's Medical Center, part of CHI St. Luke's Health. Currently, Baylor has more than 3,000 trainees in medical, graduate, nurse anesthesia, physician assistant, orthotics and genetic counseling as well as residents and postdoctoral fellows. Follow Baylor College of Medicine on Facebook and Twitter.

Osaka University

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