Insights into molecular process of sperm production may shed light on male infertility microbiologystudy

A genetic mutation in mice affects cells required for sexual reproduction and holds clues about male infertility that could pave the way for new treatments and male contraceptives, a Rutgers University–New Brunswick researcher and colleagues have discovered.

Writing in Nature Communications, researchers led by Devanshi Jain, an assistant professor with the Department of Genetics at the School of Arts and Sciences, address a fundamental question about how humans and animals develop germ cells that go on to form sperm.

“We discovered that when mouse germ cells aren’t properly connected to each other by intercellular bridges—links between cells that allow for communication and exchange of resources—they are unable to complete many of the processes necessary for development and survival, such as replicating their DNA and repairing DNA breaks,” Jain said.

In the United States, more than 11% of men under the age of 49 are infertile. While the causes are varied and range from infections to hormonal imbalances, deformities during meiosis—a specialized cell division process that creates sperm and eggs—is a leading cause. Jain’s lab specializes in identifying and studying meiotic defects in mice.

These findings add to a cannon of research aimed at decoding reproductive defects, in particular, how reproductive cells repair DNA damage.

“Filling these knowledge gaps will help us understand the genetic basis of infertility, which we need to know to be able to come up with treatments, improve diagnoses, or even someday be able to successfully reproduce this developmental process in vitro,” she said.

Future research could even help develop a male contraceptive.

“One day, men might be able to receive a small molecule that would deplete sperm but be reversible,” Jain said.

Researchers have long understood that cell connectivity via intercellular bridges is important for producing sperm. They also have understood that a testis gene, TEX14, helps modulate the formation of intercellular bridges. When this gene is absent, the intercellular connections don’t form properly, resulting in a block in meiosis culminating in infertility.

What remained poorly understood were the exact roles that intercellular bridges played in meiosis, and what made them so indispensable. This research addresses some of these gaps.

Jain and colleagues compared mice with a completely nonfunctional TEX14 gene, thus having no intercellular bridges, to those with a novel TEX14 mutation that results in partial depletion of bridges. This enabled the researchers to “dissect the functions” of intercellular bridges during the process of meiosis, Jain said.

“The collection of defects accumulated during meiosis in mice with defective intercellular bridges results in germ cell death, which leads to infertility. Our findings demonstrate that proper regulation of meiosis requires cell connectivity and establish a new framework for how we think about its control in the male germline.”

The findings add to researchers’ understanding of male infertility by shedding light on the series of complex cellular developmental transitions that culminate in the production of sperm.

Mice aren’t the only creatures dependent on these “cytoplasmic channels” for sexual reproduction. Flies also have intercellular bridges for the sharing of information and resources, and other species demonstrate similar methods of connectivity during meiosis.

“Germ cell connectivity appears to be a critical part of germ cell development,” said Jain.

Still, there is much to learn before those scientific hurdles are cleared.

“No one gene is going to solve male infertility; there are hundreds of genes involved in making meiosis happen properly,” Jain said. “This is just one more piece in a very complicated puzzle.”