Sperm gene discovery may lead to non-hormonal male contraceptive

The discovery of a gene that enables sperm to mature may lead to the development of a non-hormonal male contraceptive, according to new research in mice, led by the University of Edinburgh, Scotland, that was published in the journal PLoS Genetics on 24 May. Currently, the only male contraceptives available rely on disrupting the production of hormones like testosterone, which can cause unpleasant side effects such as acne, irritability and mood swings. First author Dr Lee Smith is Reader in Genetic Endocrinology at the University of Edinburgh's Centre for Reproductive Health. He told the media: "If we can find a way to target this gene in the testes, we could potentially develop a non-hormonal contraceptive." The gene, called Katnal1, is critical to enabling sperm to mature in the testes. Finding a way to regulate the gene could potentially stop the sperm maturing and render them ineffective. Not only could this form the basis of a new type of male contraceptive that does not involve disrupting hormone levels, it could also lead to new treatments for male infertility caused by a faulty Katnal1 gene. "The important thing is that the effects of such a drug would be reversible because Katnal1 only affects sperm cells in the later stages of development, so it would not hinder the early stages of sperm production and the overall ability to produce sperm," explained Smith. "Although other research is being carried out into non-hormonal male contraceptives, identification of a gene that controls sperm production in the way Katnal1 does is a unique and significant step forward in our understanding of testis biology," he added. The production and maturation of sperm cells is a complex process that relies on key interactions between germ cells and supporting mechanisms, including a "scaffolding" structure made of microtubules that allows nutrients and other compounds essential to sperm health and growth to travel to the germ cells. The authors write that it is well established that an essential component of male fertility is a process that breaks down and rebuilds the microtubules, which allows the sperm cells to move within the testes as they mature. But until now, nobody knew which gene was responsible for this process. In their study, Smith and colleagues discovered that when they knocked out the Katnal1 gene in male mice it rendered them infertile. They found that Katnal1 is expressed in the testicular Sertoli cells (SC) that support germ cell maturation and that "consistent with chemical disruption models, loss of function of KATNAL1 leads to male-specific infertility through disruption of SC microtubule dynamics and premature exfoliation of spermatids from the seminiferous epithelium". Thus they established that Katnal1 is the essential controller of the process that regulates the microtubule scaffolding structure. In their discussion, Smith and colleagues describe Katnal1 as an essential promoter of male fertility, and discovering how it behaves within the testicular Sertoli cells "represents an important first step towards understanding the molecular mechanisms underlying SC microtubule remodelling". "Such information will be of utility both for increasing our understanding of male infertility and the development of treatments and non-hormonal male contraceptives," they conclude. Grants from the UK Medical Research Council and the National Health and Medical Research Council of Australia helped finance the study.