Gene Discoveered That Drives Fertility in Male Mice

Workers in the laboratory of Richard Freiman, associate professor of medical science at Brown University have discovered a specific gene in human males that seems to be essential to sperm production later in life.

A paper published in the journal Stem Cells details how the loss of a protein called TAF4b in male mice causes premature infertility. According to Freiman, mutations that prevent the continuous production of TAF4b leave mice incapable of sustaining spermatogenesis after only a few months of sexual maturity.

This study began when Freiman’s team discovered that TAF4b was expressed at high levels in the ovaries and the testes. Later, Freiman and his colleagues used homologous recombination to specifically modify the TAF4b gene. Freiman explained that homologous recombination can “knock specific genes out of the mouse genome,” after which you can “examine the mice that are born and see what function the gene serves in normal development.” Such experiments showed that male mice whose TAF4b gene was synthetically modified so that it expressed TAF4b initially, but did not sustain its expression were only fertile for a month or two, whereas mice with intact TAF4b remained fertile for several years.

“Cells that are involved in initial fertility are different than cells involved in subsequent rounds of sperm production. The first set undergoes meiosis and become sperm by a direct route, but the other set develops into precursor cells that become stem cells,” Freiman said. “What we hypothesized about our mice is that they’re able to go through this initial round of spermatogenesis, but they can’t make the stem cell population, so they can’t set themselves up for long-term fertility,” he added.

Since humans have a TAF4b gene that is very similar to the mouse gene, the results of Freiman’s laboratory might be applicable to human fertility, said Eric Gustafson, a postdoctoral research fellow in Freiman’s laboratory and first author of the paper.

These results interact with another study that was published last year that examined a population of four infertile brothers in eastern Turkey; each of whom each had a homozygous mutation in their TAF4b gene similar to the one created in the mice. According to Gustafson, these men had very low or no sperm counts. “So we think these genes have many similar, if not identical functions in humans. What we learn about in the mouse gene may be used to address or diagnose reproductive defects in humans as well,” he added.

With couples having children later and later in life, this study has important implications for family planning. “If we could learn how this process is regulated normally, clinicians might be able to devise better strategies to either monitor or even intervene with cases of infertility,” said Freiman. To give an example, Freiman suggested that if scientists could detect the mutation in teenage boys early on, then doctors could freeze their patients’ sperm for later in life.

The study also has important outcomes in terms of stem cell research, said Professor of Biology Gary Wessel, who was not involved in the study. “This research shows us that this particular transcription factor, TAF4b, is involved in the transcription process involved in maintaining the stem cell itself,” Wessel said. “As a consequence, it now gives the investigators a more careful view of what stem cell decisions are like,” he added.

The study’s results are relevant to all stem cell research, Wessel said. “Everything in biology is connected. If you make any kind of breakthrough, it’s going to have ripple effects throughout the entire discipline.”

How does TAF4b affect fertility? That’s the next goal of Freiman’s research. Freiman said. “We now know that TAF4b performs this function, but we don’t know how it does it,” he added. “Once we figure that out, it might reveal new areas of intervention for fertility preservation.”

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).