Nav: Home

Underappreciated protein plays critical role in RNA regulation and male fertility

March 31, 2016

A protein once thought to be of little consequence has been found to be a central player in processes ranging from male fertility to early embryonic development, according to a study published in the March 31 online issue of Cell by researchers at the University of California, San Diego School of Medicine.

"We've obtained several lines of evidence that the UPF3A protein is a potent suppressor of the nonsense-mediated RNA decay (NMD) pathway," said Miles Wilkinson, PhD, senior author and professor in the Department of Reproductive Medicine at UC San Diego School of Medicine. "UPF3A was previously thought to be just the opposite -- a promoter of the NMD pathway, but a weak one that had little effect. Thus, UPF3A was largely ignored by the field."

The NMD pathway is a critical quality control mechanism used by cells to eliminate faulty messenger RNAs (mRNAs) - the molecules responsible for transmitting genetic code. If not degraded, these aberrant mRNAs lead to the formation of short versions of proteins that can raise havoc in cells. "By preventing the production of these truncated proteins, NMD is thought to protect against many diseases, including cancer, diabetes and a wide variety of genetic diseases," said Wilkinson.

To increase the effectiveness of the NMD pathway, Wilkinson said, drugs could be designed to inhibit UPF3A, as it is a natural suppressor of the pathway. Diseases that could potentially be treated include diabetes, amyotrophic lateral sclerosis and Marfan syndrome, a genetic disease of the connective tissue.

"Since 15 to 30 percent of all human genetic diseases are caused by mutations detected by NMD, the range of genetic diseases potentially treatable by 'NMD therapy' is vast," said Samantha Jones, a PhD student in Wilkinson's lab who is co-first author on the study.

Because UPF3A is highly expressed in male testes, the researchers also explored whether UPF3A might have a role in fertility. In mouse experiments, they knocked out UPF3A in male germ cells -- the cells that give rise to sperm -- and found these mutant mice generated few sperm.

The researchers found that loss of UPF3A greatly reduced the number of cells in the testes that undergo meiosis, a process unique to the cells that give rise to sperm and eggs. "While more study is needed, it is possible that loss of UPF3A causes a defect in the meiosis process itself," said Wilkinson.

The research team also globally knocked out UPF3A in mouse models and found this led to early embryonic death. "This suggests that the NMD inhibitory function of UPF3A is also crucial in the very first stages of development in embryos," said Jones.

"Another twist to this story is that UPF3A has a sister protein called UPF3B, which is encoded by the X chromosome and is critical for normal human cognition," said Wilkinson. Its loss in humans causes intellectual disability and is highly linked to neurodevelopmental disorders, like autism and schizophrenia.

Unlike UPF3A, UPF3B is an activator of the NMD pathway. Wilkinson said this has evolutionary implications since the two genes that give rise to these two proteins come from a single gene that duplicated approximately 500 million years ago, when the vertebrates first appeared.

"While it is well accepted that gene duplication drives the generation and adaptation of species, it remains a poorly understood evolutionary force," Wilkinson said. Particularly mysterious has been what prevents newly duplicated genes from deteriorating. Wilkinson and colleagues discovered a simple mechanism that likely allowed the duplicated UPF3A gene to avoid decay 500 million years ago. It lost sequences essential for activity and became a repressor. "At a genetic level, it's a lot easier to lose something than gain something."

The finding that UPF3A and UPF3B have opposite effects suggests they are the product of a relatively rare evolutionary outcome of gene duplication -- functional antagonism. UPF3B turns NMD "on" while UPF3A turns NMD "off."

But why does NMD have such an "on" and "off" switch? A likely answer comes from the well-established finding that NMD is not only a quality control mechanism, but also a pathway that degrades many normal mRNAs. "By degrading batteries of mRNAs encoding proteins at specific points in development, NMD can potentially greatly influence development," said Wilkinson.

Indeed, many laboratories have found that NMD is critical for the development of several cell types in organisms ranging from flies to humans. "Our results suggest that UPF3A and UPF3B act as volume controls to up- and down-regulate NMD at the right times for normal development to proceed," Wilkinson said.
-end-
Co-authors include: first author, Eleen Y. Shum, Cellular Research, Inc.; Ada Shao, Jennifer Dumdie, Matthew D. Krause, Chih-Hong Lou, Josh L. Espinoza, Hye-Won Song, Mimi H. Phan, Madhuvanthi Ramaiah, Lulu Huang, and Heidi Cook-Andersen, UC San Diego; Wai-Kin Chan, University of Texas MD Anderson Cancer Center; John R. McCarrey, University of Texas at San Antonio; Kevin J. Peterson, Dartmouth College; and Dirk G. De Rooij, Utrecht University, The Netherlands.

This research was funded, in part, by the National Institutes of Health grant (GM111838).

University of California - San Diego

Related Fertility Articles:

Fertility preservation use among transgender adolescents
Transgender adolescents often seek hormonal intervention to achieve a body consistent with their gender identity and those interventions affect reproductive function.
A new way to assess male fertility
Current tests for male fertility include measuring the concentration and motility of spermatozoa.
Male fertility after chemotherapy: New questions raised
Professor Delbès, who specializes in reproductive toxicology, conducted a pilot study in collaboration with oncologists and fertility specialists from the McGill University Health Centre (MUHC) on a cohort of 13 patients, all survivors of pediatric leukemia and lymphoma.
Vaping may harm fertility in young women
E-cigarette usage may impair fertility and pregnancy outcomes, according to a mouse study published in the Journal of the Endocrine Society.
Are fertility apps useful?
Researchers at EPFL and Stanford have carried out an analysis of the largest datasets from fertility awareness apps.
Marijuana and fertility: Five things to know
For patients who smoke marijuana and their physicians, 'Five things to know about ... marijuana and fertility' provides useful information for people who may want to conceive.
How could a changing climate affect human fertility?
Human adaptation to climate change may include changes in fertility, according to a new study by an international group of researchers.
Migrants face a trade-off between status and fertility
Researchers from the universities of Helsinki, Turku and Missouri as well as the Family Federation of Finland present the first results from a new, extraordinarily comprehensive population-wide dataset that details the lives of over 160,000 World War II evacuees in terms of integration.
Phthalates may impair fertility in female mice
A phthalate found in many plastic and personal care products may decrease fertility in female mice, a new study found.
Climate change damaging male fertility
Climate change could pose a threat to male fertility -- according to new research from the University of East Anglia.
More Fertility News and Fertility Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.