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(LEFT) Germ cells (green) of mice having the TAF4b gene. (RIGHT) Mice lacking the TAF4b gene make fewer germ cells (green). This leads to decreased sperm production after about a month of initial fertility. Image Credit: Freiman lab/Brown University

A mutation that can cause male infertility

Brown University biologists have determined how the loss of a gene results in infertility in mice. Their work in the complex process of sperm generation may directly apply to a similar loss of fertility in men.

The research team discovered the loss of a gene that generates the protein TAF4b decreases the number of embryonic progenitor cells in a male mouse's reproductive system. Lacking these important cells means the mice, fertile at first, quickly deplete their limited sperm supply and cannot generate new sperm.

"Mice can usually reproduce until they are two years old [dying at about 2.5 years], but these mice can only reproduce until they are four months old," said Richard Freiman, senior author of the new study in the journal Stem Cells.

Absence of the TAF4b protein has profound impacts on the reproductive system, as it affects how genes are regulated and transcribed into RNA, the first step in gene "expression." In previous work, Freiman's group found that female mice without TAF4b are totally infertile with ovaries that age prematurely. In experiments with males, the effect was more subtle.

Sperm generation follows a complex chain of events that begins before a male mouse is born. Researchers comparing the development of mice with and without the TAF4b gene, found mice with TAF4b, have made progenitor cells for sperm production while still embryos. These cells continue to proliferate normally, laying the groundwork in the testes for a robust pool of spermatogonial stem cells. Stem cells continue to produce a renewable supply of sperm throughout the greater part of the mouse life span.

But in mice without TAF4b, there are fewer progenitor cells and consequently fewer stem cells. The stem cells produced sperm in the months following birth, but were unable to self renew nor produce sperm for the sexually mature life span of the mice. Ultimately the testes, which appeared to have developed normally at birth, became unproductive and atrophy.

Not only do humans share a gene for TAF4b with mice, but a 2014 study in the Journal of Medical Genetics provided similar evidence regarding low sperm counts in men with the mutation. Four Turkish brothers carrying a mutation in the TAF4b gene each had low sperm counts. Their mutation appears in the same gene region as that in the mice in Freiman's laboratory. Freiman adds: "It is possible that those men, as teenagers, were able to make functional sperm."

If the TAF4b mutation theory is supported through continued research to have the same causal relationship in humans as has been found in mice, detecting that mutation in teenage boys would allow them the opportunity to freeze sperm for when they want to become fathers.

"Developmental processes that occur in embryogenesis have a profound affect on the ability of adult organ systems to function properly.

Abstract
Long-term mammalian spermatogenesis requires proper development of spermatogonial stem cells (SSCs) that replenish the testis with germ cell progenitors during adult life. TAF4b is a gonadal-enriched component of the general transcription factor complex, TFIID, which is required for the maintenance of spermatogenesis in the mouse. Successful germ cell transplantation assays into adult TAF4b-deficient host testes suggested that TAF4b performs an essential germ cell autonomous function in SSC establishment and/or maintenance. To elucidate the SSC function of TAF4b, we characterized the initial gonocyte pool and rounds of spermatogenic differentiation in the context of the Taf4b-deficient mouse testis. Here we demonstrate a significant reduction in the late embryonic gonocyte pool and a deficient expansion of this pool soon after birth. Resulting from this reduction of germ cell progenitors is a developmental delay in meiosis initiation, as compared to age-matched controls. While GFRα1+ spermatogonia are appropriately present as Asingle and Apaired in wild type testes, TAF4b-deficient testes display an increased proportion of long and clustered chains of GFRα1+ cells. In the absence of TAF4b, seminiferous tubules in the adult testis either lack germ cells altogether or are found to have missing generations of spermatogenic progenitor cells. Together these data indicate that TAF4b-deficient spermatogenic progenitor cells display a tendency for differentiation at the expense of self-renewal and a renewing pool of SSCs fail to establish during the critical window of SSC development. This article is protected by copyright. All rights reserved.

In addition to Freiman, Lovasco and Gustafson, other authors are Kimberly Seymour of Brown and Dirk G. de Rooij of the Univerisity of Amsterdam.

The Ellison Medical Foundation and the National Institutes of Health (grant 1F32HD077986) supported the research.

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