Fertility genes required for sperm stem cells
- September 27, 2016
- University of California San Diego Health Sciences
- The underlying cause of male infertility is unknown for 30 percent of cases. In a pair of new studies, researchers have determined that the reproductive homeobox (RHOX) family of transcription factors — regulatory proteins that activate some genes and inactivate others — drive the development of stem cells in the testes in mice. The investigators also linked RHOX gene mutations to male infertility in humans.
The underlying cause of male infertility is unknown for 30 percent of cases. In a pair of new studies, researchers at University of California San Diego School of Medicine determined that the reproductive homeobox (RHOX) family of transcription factors — regulatory proteins that activate some genes and inactivate others — drive the development of stem cells in the testes in mice. The investigators also linked RHOX gene mutations to male infertility in humans. The mouse study is published September 27 by Cell Reports and the human study was published September 15 by Human Molecular Genetics.
“Infertility in general, and especially male fertility, gets little attention considering how common of a problem it is — about 15 percent of couples are affected, and nearly half of these cases are due to male infertility,” said Miles Wilkinson, PhD, professor of reproductive medicine at UC San Diego School of Medicine and senior author of the Cell Reports study. “That means around 7 percent of all males of reproductive age — nearly 4 million men in the U.S. — have fertility problems.” Wilkinson is also a co-author of the Human Molecular Genetics study, which was led by Jörg Gromoll, PhD, at the University of Münster in Germany.
Sperm are made from cells that undergo many stages. Transcription factors have been identified that direct most of these cell stages, from the dividing cells in the embryo to the cells that rearrange and partition the chromosomes to individual “pre-sperm” in the testes. However, before this latest research, Wilkinson said no transcription factors were known to direct one of the most critical stages — the formation of the stem cells in the testes, known as spermatogonial stem cells.
In the Cell Reports study, Wilkinson and team removed the entire cluster of 33 Rhox genes in mice. They were surprised to find that the most notable defect in these mice was a deficiency in spermatogonial stem cells. Hye-Won Song, PhD, assistant project scientist in Wilkinson’s lab and first author of the Cell Reports study, removed just one of the Rhox genes — Rhox10 — and found essentially the same defect as deleting the full …………read more
Fertility: Out of gas and low on sperm?
Genetic key to self-renewal of reproductive cells uncovered
- December 27, 2016
- Kyoto University
- Sperm are constantly replenished in the adult male body. Understanding the workings of stem cells responsible for this replenishment is expected to shed light on why male fertility diminishes with age, and possibly lead to new treatments for infertility.
Sperm are constantly replenished in the adult male body. Understanding the workings of stem cells responsible for this replenishment is expected to shed light on why male fertility diminishes with age, and possibly lead to new treatments for infertility.
“So-called Myc genes play an important role in stem cells’ ability to self-renew,” explains Kyoto University’s Takashi Shinohara, who is interested specifically in spermatogonial stem cells (SSCs), which are responsible for producing sperm. Shinohara adds that SSCs are unique, because they are “the only stem cells that transmit genetic information to offspring.”
In a new report in Genes & Development, the Shinohara lab demonstrates how the Myc gene regulates the self-renewal of mouse SSCs, via a process of glycolysis control. Glycolysis is a key part of cells’ energy-making mechanism.
The scientists injected two types of SSCs into mouse testes: normal cells in some, and Myc gene-suppressed in others. Two months later, they found that the total number of abnormal SSCs was far fewer than normal ones. Gene analysis showed that the capacity for self-renewal had been compromised, with possibly important implications for sperm production in these mice.
“We found changes in the expression of genes that would slow the cell cycle,” says Shinohara.
In other words, suppressed SSCs could self-renew, but at a slower than normal rate. Further study showed that this diminished rate was accompanied by impaired glycolysis, suggesting that the cells were not generating sufficient energy.
“A difference in glycolysis could explain natural differences in SSC self-renewal between mice,” elaborates Mito Kanatsu-Shinohara, first-author of the paper. “DBA/2 and B6 are two mouse types in which SSCs are know to self-renew at different rates.”
Further experiments confirmed that glycolysis was more active in the cells of DBA/2 mice. Moreover, isolating cells from B6 mice and treating them with certain chemicals that enhanced glycolysis could increase the proliferation rate to levels comparable with DBA/2.
“These findings could have important implications for infertility research in the future,” says Shinohara. “Stimulating the metabolism of SSCs could improve their proliferation. However, more careful study of the molecular pathways is necessary.”