It is impossible to imagine mammalian reproduction without the fusion of male and female gametes. The process of fertilization is fascinatingly complex and is a culmination of several physical and biochemical mechanisms. Some of these provide the sperm with the ability to fertilize the egg and are known to affect male fertility. Now, scientists have found that a signaling molecule plays a crucial role in male fertility and enabling the sperm to successfully fuse with the ovum.
A new study by researchers from the University of California San Diego has found that a protein known as Girdin (GIV) is vital in the occurrence of two processes— capacitation and acrosome reaction (AR)—that are essential in promoting sperm motility, survival, and successful fertilization. The research was published in the journal eLife
"The findings demonstrate how GIV orchestrates distinct signaling programs in sperm that are separated by space and time, effectively supporting capacitation while inhibiting premature AR. As a result, GIV plays an essential role in male fertility," said Dr. Pradipta Ghosh, lead author of the study, in a statement.
Undergoing Changes to Fertilize Eggs
It is not a straightforward journey for sperm in its pursuit of reaching the egg and fertilizing it. Though it may sound simple, an onward journey towards the ovum after insemination, sperm have to undergo physical and chemical changes before they can acquire the ability to unite with the egg. Two processes endow the sperm with these capacities—capacitation and acrosome reaction (AR).
The process of capacitation physiologically transforms spermatozoa. It changes the membrane of the head in order to enable its penetration of the hard outer layer of the egg known as zona pellucid. Capacitation also alters the chemistry of the tail in order to induce higher motility, or the ability to swim.
AR, which follows Capacitation, is a chemical process that is associated with the release of enzymes within the head of the spermatozoa. This further magnifies their penetrative ability to breach the zona pellucid. Importantly, AR is time-dependent (i.e) it cannot occur prematurely or late. Premature AR has been linked to idiopathic, or spontaneous male infertility. However, in terms of the fundamental molecular mechanisms involved, neither of the processes are adequately comprehended.
GIV's Role In Male Infertility
When GIV was discovered in 2005, the full length of the protein was found to be highly expressed in the brain and the testis. For the study, the author studied mice and human sperm and testis. They observed that GIV—a protein belonging to the 'G proteins' (also known as guanine nucleotide-binding proteins) family—regulates the actions of enzymes that switch the processes of capacitation and AR on and off. G proteins, in general, function as molecular switches within cells, and transmit signals to the interior of a cell from various stimuli outside it.
The team noted that GIV is quickly phosphoregulated (regulation via phosphorylation) on residues of two amino acids—serine and tyrosine—in human and mice spermatozoa. Phosphorylation is the biochemical process through which phosphate is added to an organic compound. It was noted that these 'phosphomodifications' gave GIV the ability to engineer two marked signaling programs in the head and tail of the spermatozoa.
In the tail, GIV amplifies PI3K→Akt signals, survival, and sperm motility. PI3K→Akt signals are an intracellular signaling pathway essential for the regulation of the cell cycle. In the head, GIV inhibits the surge of cAMP (Cyclic adenosine monophosphate)—a 'second messenger' important in several biological processes—and premature AR. Additionally, GIV transcripts were found to be downregulated in the semen and testis of infertile men.
Potential to Overcome Infertility
About 12 to 15 percent of couples are unable to conceive worldwide. Studies have found that males contribute to around half the number of cases. There are multiple causes for male infertility. However, approximately 25 percent of male infertility involves either sperm transportation disorders or idiopathic (unknown) factors in the sperm with no obvious dysfunction.
Therefore, the researchers state that the findings of the study provide crucial insights into male infertility. "We've found evidence that GIV may perform different roles in the capacitation of sperm, findings that shed new light on both how defective GIV-signaling might 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 by promoting premature acrosome reaction," asserted Dr. Ghosh.
She also added that this involvement of GIV may help in devising male contraception. "The latter, ironically enough, may be a promising strategy for development of a male contraceptive pill specifically targeting sperm," she concluded.
