AsianScientist (May. 22, 2023) – Sperm defects and dysfunction are some of the common causes of male infertility. A recent study from Japan has unlocked new knowledge about the process by which sperms mature before they are capable of fertilizing an egg. The findings, published in Nature Communications, can not only help advance treatment of male infertility but also potentially meet the growing need for effective and safe male contraceptives.
Sperm formed in the testes may appear to have their distinct tadpole-like structure, but they still need to get fine-tuned for their role in creating a new life. For this, they must travel through a highly-coiled structure known as the epididymis. The specialized environment of the epididymis along with special factors secreted from the testes are essential for sperm to mature. But to date, scientists have not been able to identify all the molecular components involved in this process, gating insights that could be crucial for understanding male infertility.
In order to understand this better, a team of researchers from Osaka University in Japan used the genome-editing tool, CRISPR-Cas9, to manipulate protein expression in experimental mouse models.
“The genetic makeup of a mouse can be altered in the lab to study molecular pathways in more detail,” explained Masahito Ikawa, senior author and professor at Osaka University. “The advent of genome-editing technology is important; before this technology was available, it was challenging to study the mechanisms of sperm maturation.”
Previous studies have already highlighted the significance of a protein secreted from the testes called NELL2 in sperm maturation. Once released, NELL2 flowed to the epididymis to bind to a protein receptor called ROS1, sparking the signal for the maturation process to begin.
The study team discovered another protein that was also important: ‘NELL2-interacting cofactor for lumicrine signaling’ (NICOL).
“We found that mice lacking NICOL were sterile, which indicates that NICOL is required for the sperm-maturation pathway to work properly,” said the lead author, Daiji Kiyozumi. “When NICOL expression was activated, fertility was restored.”
In the absence of NICOL, the walls of the epididymis failed to undergo the necessary specialization that is vital to influence sperm maturation. As a consequence, the sperm from these mice showed abnormalities and were unable to migrate through the female reproductive tract of female mice after ejaculation.
Interestingly, the researchers also found that NICOL and NELL2 functioned as a ‘dynamic duo’. NICOL formed a tight complex with NELL2 before binding to the ROS1 receptor. This suggested NICOL plays a key role in controlling NELL2-ROS1 mediated signaling for the sperm-maturation process to succeed.
These new insights into sperm maturation process hold promising implications for advancing the treatment of male infertility. They also offer exciting potential for addressing the need for safer male contraceptives. Hormone-based male contraceptives often bring out undesirable side effects due to the modulation of testosterone levels, which can impact body and muscle mass. Isaka and his team suggested that disrupting the interaction between NICOL, NELL2 and ROS1 could pave the way for the development of non-hormonal male contraceptives with fewer unintended effects.
To determine the viability of these implications, the next step would be to find out if similar results can be obtained in human cells and tissues.
Source: Osaka University ; Image: Shutterstock
The article can be found at A small secreted protein NICOL regulates lumicrine-mediated sperm maturation and male fertility.
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