Key regulator of sperm maturation revealed as a target for male infertility treatments

Scientists demonstrated that NELL2, a factor release by the testis, is essential for sperm to mature into motile cells able to fertilise an egg.

blue sperm on a black background

Research has revealed how a lack of communication between the testis and epididymis may lead to male infertility.

The team discovered that a novel testicular luminal protein, NELL2, triggers a chain of events in the epididymis that matures spermatozoa into sperm, allowing them to be motile.

Producing mature sperm

Spermatozoa (an immature form of sperm) are produced in the seminiferous tubules of the testis and move through the epididymis, a long, convoluted tube linked to the vas deferens (the duct that moves sperm from the testicle to the urethra). When the sperm enter the epididymis as spermatozoa, they are not motile and are incapable of fertilisation. However, in their passage through the epididymis, the spermatozoa are provided an appropriate environment for maturation and storage as sperm pending ejaculation.

Scientists have hypothesised that proteins released by the testis early in this process act upon the epididymis to mature the sperm.

“Until now the proteins working through the lumicrine system of signalling 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,” said Dr Martin Matzuk, professor and director of the Center for Drug Discovery at Baylor College of Medicine, US.

Identifying NELL2

In their research, the scientists focused on NELL2, a protein factor secreted by testicular germ cells, as a possible 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,” explained lead author Dr Daiji Kiyozum. “Moreover, their infertility could be rescued with a germ-cell-specific transgene, thus excluding other sites of expression. We also illustrated lumicrine signalling by demonstrating tagged NELL2 in the epididymal lumen.”

In their paper published in Science, the team reported that spermatogenesis (the process of producing sperm) proceeds normally in NELL2 knockout mouse testes but their epididymis was poorly differentiated. The same was seen in ROS1 knockout mice.

Following mating, neither NELL2 knockout nor ROS1 knockout spermatozoa entered the uterine tubes or fertilised an egg. Further investigation showed that the NELL2 knockout epididymis is incapable of processing a specific sperm surface protein essential for male fertility.

Implications for male fertility

Elaborating on their study, both senior authors (Matzuk and Dr Masahito Ikawa with Osaka University, Japan), said, “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.”

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