Nav: Home

A critical enzyme for sperm formation could be a target for treating male infertility

March 25, 2020

While some of our body's cells divide in a matter of hours, the process of making sperm, meiosis, alone takes about 14 days from start to finish. And fully six of those days are spent in the stage known as the pachytene, when pairs of chromosomes from an individual's mother and father align and connect.

"This stage is really important, because the pair needs to be aligned for the exchange of genetic material between those two chromosomes," says P. Jeremy Wang, a biologist in Penn's School of Veterinary Medicine. "If anything goes wrong at this stage, it can cause a defect in meiosis and problems in the resulting sperm, leading to infertility, pregnancy loss, or birth defects."

In a new paper in Science Advances, Wang and colleagues have identified an enzyme that plays a crucial role in maintaining this chromosomal pairing during the pachytene stage of meiosis. Without this protein, named SKP1, meiosis cannot proceed to metaphase, the next major developmental stage involved in generating sperm cells.

The finding may help overcome hurdles that have stood in the way of treating certain forms of male infertility, in which a man makes no sperm but in whom sperm's precursor cells, spermatogonia, can be found.

"Reproductive technologies like in vitro fertilization have made a huge difference for infertile patients, but the male needs to have at least some sperm," says Wang. "If the male has no sperm, then the only option is to use donor sperm. But if you can find these spermatogonia, the pre-meiotic germ cells, they could be induced to go through meiosis and make sperm. So SKP1 could be part of the solution to ensuring meiosis continues."

Wang is also hopeful that his finding could aid in basic research on sperm development that his and many other labs pursue.

"Right now we use animals to do our research; we don't have a cell culture system to produce sperm," he says. "Manipulating SKP1 and the pathway in which it acts could allow us to set up an in vitro system to produce sperm artificially, which would be a boon for our studies."

The publication represents nearly a decade of work, led by Wang's postdoctoral researcher Yongjuan Guan, with major contributions from former postdoc Mengcheng Luo.

The team began focusing on SKP1 after conducting a screening test to look for proteins found in the area where the paired chromosomes come together during the pachytene stage of meiosis. From earlier studies, the researchers knew that SKP1 also plays a role in cell division in cells throughout the body, not just sperm and eggs. Without it, cells die.

That fact forced the Penn Vet team to get creative to understand the protein's function. Unable to simply eliminate it, they created a model system in mice in which they could turn off the protein only in the germ cells and only in adulthood.

"Taking this inducible, germ-cell-specific model, we found that taking away SKP1 caused the chromosomes to prematurely separate," says Wang.

While the normal alignment process in the pachytene stage takes six days in mice, in the cells that lost SKP1 the paired chromosomes separated far earlier.

Scientists had hypothesized the existence of a metaphase competence factor, or some protein required for a cell to enter metaphase. Wang believes that SKP1 is it.

While introducing a compound known as okadaic acid to sperm precursor cells can coax them into an early entrance to metaphase, cells lacking SKP1 did not progress to metaphase.

Experiments in developing eggs showed the researchers that SKP1 is also required for females to maintain viable eggs. Oocytes, the cells that develop through meiosis to form mature eggs, that lacked SKP1 developed misaligned chromosomes and many eventually were lost.

In future work, Wang and his colleagues want to dig deeper into the mechanism of action by which SKP1 works to ensure cells can progress to metaphase, with the idea of eventually manipulating it to find strategies for addressing infertility and innovative laboratory techniques.

"Now that we know SKP1 is required, we're looking for the proteins it interacts with upstream and downstream so we can study this pathway," says Wang.
-end-
Wang, Guan, and Luo's coauthors on the paper were Penn Vet's N. Adrian Leu, Jun Ma, and Gordon Ruthel; Penn School of Arts and Sciences Biology Department's Lukás Chmátal and Michael Lampson; and Cornell University's Jordana C. Bloom and John C. Schmienti. Luo is now a faculty member at China's Wuhan University.

Support for the work came from the National Institute of General Medical Sciences (grants GM118052 and GM122475), National Key Research and Development Program of China (Grant 2018YFC1003400), National Natural Science Foundation of China (Grant 31771588), Thousand Youth Talents Plant, and National Institute of Child Health and Human Development (grants HD082568 and HD057854).

University of Pennsylvania

Related Chromosomes Articles:

GPS for chromosomes: Reorganization of the genome during development
The spatial arrangement of genetic material within the cell nucleus plays an important role in the development of an organism.
Extra chromosomes in cancers can be good or bad
Extra copies of chromosomes are typical in cancerous tumor cells, but researchers taking a closer look find that some extra copies promote cancer growth while others actually inhibit cancer metastasis.
Scientists detail how chromosomes reorganize after cell division
Researchers have discovered key mechanisms and structural details of a fundamental biological process--how a cell nucleus and its chromosomal material reorganizes itself after cell division.
X marks the spot: recombination in structurally distinct chromosomes
A recent study from the laboratory of Stowers Investigator Scott Hawley, PhD, has revealed more details about how the synaptonemal complex performs its job, including some surprising subtleties in function.
How chromosomes change their shape during cell differentiation
Scientists from the RIKEN Center for Biosystems Dynamics Research have provided an explanation of how chromosomes undergo structural changes during cell differentiation.
Key similarities discovered between human and archaea chromosomes
A study led by Indiana University is the first to reveal key similarities between chromosomes in humans and archaea.
Science snapshots: Chromosomes, crystals, and drones
From Berkeley Lab: exploring human origins in the uncharted territory of our chromosomes; scientists grow spiraling new material; drones will fly for days with this new technology
Human artificial chromosomes bypass centromere roadblocks
Human artificial chromosomes (HACs) could be useful tools for both understanding how mammalian chromosomes function and creating synthetic biological systems, but for the last 20 years, they have been limited by an inefficient artificial centromere.
Does rearranging chromosomes affect their function?
Molecular biologists long thought that domains in the genome's 3D organization control how genes are expressed.
Super-resolution microscopy illuminates associations between chromosomes
Thanks to super-resolution microscopy, scientists have now been able to unambiguously identify physical associations between human chromosomes.
More Chromosomes News and Chromosomes 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

Uncharted
There's so much we've yet to explore–from outer space to the deep ocean to our own brains. This hour, Manoush goes on a journey through those uncharted places, led by TED Science Curator David Biello.
Now Playing: Science for the People

#555 Coronavirus
It's everywhere, and it felt disingenuous for us here at Science for the People to avoid it, so here is our episode on Coronavirus. It's ok to give this one a skip if this isn't what you want to listen to right now. Check out the links below for other great podcasts mentioned in the intro. Host Rachelle Saunders gets us up to date on what the Coronavirus is, how it spreads, and what we know and don't know with Dr Jason Kindrachuk, Assistant Professor in the Department of Medical Microbiology and infectious diseases at the University of Manitoba. And...
Now Playing: Radiolab

Dispatch 1: Numbers
In a recent Radiolab group huddle, with coronavirus unraveling around us, the team found themselves grappling with all the numbers connected to COVID-19. Our new found 6 foot bubbles of personal space. Three percent mortality rate (or 1, or 2, or 4). 7,000 cases (now, much much more). So in the wake of that meeting, we reflect on the onslaught of numbers - what they reveal, and what they hide.  Support Radiolab today at Radiolab.org/donate.