Mammalian sperm cannot fertilize an egg right from the start. It is a skill acquired only after insemination, during the passage through the female reproductive system, and requires two consecutive, time-sensitive processes to provide sperm with the physical and biochemical characteristics necessary to complete their fundamental work. The first process is called capacitation, which alters the physiology of each sperm, modifying the membrane of the head to help it penetrate the hard, outer layer of an egg and chemistry in the tail to generate greater motility, the ability to move. and swim. The second process is the acrosome reaction (ACR), a chemical action that involves the release of enzymes in the head of the sperm that further increase the penetration of the zona pellucida. Both processes are essential for successful egg fertilization, and ACR is time-dependent – it can’t happen too early or too late. Indeed, premature ACR has been associated with idiopathic (spontaneous) male infertility.
Neither process, however, is well understood in terms of the underlying molecular mechanisms involved. In a new article, published in the journal eLife, a team of researchers from the University of California San Diego School of Medicine, led by senior author Pradipta Ghosh, MD, professor in the departments of Medicine and Cellular and Molecular Medicine, details how GIV / Girdin, a ubiquitous signaling molecule, plays a vital role in male fertility, orchestrating the ability and ACR to promote sperm motility, survival and fertilization success. Specifically, the team found that GIV, a member of the G protein family that acts as molecular switches within cells, regulates the activity of enzymes that activate and deactivate capacitance and ACR processes. The receptor is transmitting tuning signals and orchestrating distinct signaling programs in spermatozoa separated by space and time, effectively supporting capacity and inhibiting premature acrosome reaction. Consequently, GIV plays an essential role in male fertility.
Infertility affects about 10% of couples globally, with males being a primary or contributing factor in about half of all cases, according to published studies. The causes of male infertility are varied, but about 25% involve sperm transport disorders or idiopathic factors in the sperm with no apparent dysfunction. In this research, the team found evidence that low levels of GIV transcripts in men are invariably associated with infertility. Additionally, GIV may play different roles in sperm capacitance, discoveries that shed new light on both how defective GIV signaling can be used as a potential marker for male infertility and how inhibitors of GIV-dependent signaling inhibit fertility by reducing sperm motility and viability and promoting a premature acrosome reaction. The latter, ironically, could be a promising strategy for developing a male contraceptive pill targeted specifically at sperm.
This is to address another serious public health and ethics problem: between 2015 and 2019, approximately 120 million unwanted pregnancies occurred worldwide each year. Although there are oral contraceptives for women, the development of oral contraceptives for men has not been successful until now. But a team from Osaka University is working on it: Using protein sequence data analysis and genome editing technology, scientists led by Professor Masahito Hikawa found that the SPATA33 protein plays an important role in regulating motility. of spermatozoa. which will help develop male contraceptives. It was previously known that calcineurin, a calcium-dependent phosphatase, plays an important role in regulating sperm motility. Calcineurin is considered a good target for male contraceptives because administering calcineurin inhibitors to male mice causes reversible infertility over a short period of time.
However, since calcineurin also has an important function in immunity, there is the problem that if calcineurin in immune cells is inhibited, immune function will also be suppressed. Therefore, the research team sought to elucidate the mechanism that regulates calcineurin function specifically in sperm. They focused on the PxIxIT motif found in many proteins that bind to calcineurin. Of the approximately 20,000 mouse proteins, eight proteins have been found that contain the PxIxIT motif and are predominantly expressed in the testis. Genome editing technology was then used to generate knockout mice for three of these proteins that had not been previously analyzed. As a result, SPATA33 knockout mice showed reduced sperm motility and fertility defects, similar to calcineurin knockout mice. Further analysis revealed that SPATA33 regulates the localization of calcineurin. When SPATA33 is eliminated, calcineurin cannot localize in the central part of the sperm tail and the central part cannot fold, leading to reduced sperm motility.
In this region, sperms contain the majority of their mitochondria, the ATP-producing powerhouses that will power their tail to move. In fact, SPATA33 causes calcineurin to be localized precisely at the mitochondrial level, which the other cellular proteins with the calcineurin-related PxIxIT protein motif do not do. Last year, Professor Hikawa’s team discovered the role of another protein involved in sperm motility, called NELL2 and secreted by sperm to act as a fertility factor, although it is not yet clearly known how it works. Using innovative genome-editing technology, the scientists generated knockout mice lacking the NELL2 gene and demonstrated that these knockout males are sterile due to a defect in sperm motility. The research team observed that spermatogenesis proceeds normally in the testes of NELL2 knockout mice, but their epididymis was poorly differentiated, similar to ROS1 receptor knockout mice. After mating, neither NELL2 knockout nor ROS1 knockout spermatozoa can enter the fallopian tubes or fertilize an egg.
Further investigations have shown that the NELL2 knockout epididymis is unable to process sperm surface enzymes, essential for male fertility, such as ovokimase 2 and metalloprotease 28. So this molecular pathway can also be investigated to find some molecule. which selectively interferes with spermatozoa. Likewise, scientists believe that targeting SPATA33 may lead to the development of male contraceptives that specifically inhibit the function of calcineurin in spermatozoa. Furthermore, the mechanism by which SPATA33 controls sperm motility was clarified in this study, adding a new perspective to the investigation and diagnosis of the cause of male infertility, as well as the problem of contraception.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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