Key protein in sperm production could aid male infertility treatments

By Lois Zoppi, B.A.Mar 26 2020

It takes approximately 14 days for sperm to be created in a process called meiosis. Six of these days are spent in the pachytene phase, during which chromosome pairs from a mother and father align and connect.

Image Credits: Christoph Burgstedt / Shutterstock.com

Researchers at the School of Veterinary Medicine have discovered that a key protein, SKP1, drives this crucial step in the sperm production process and facilitates cell division, which may help infertile couples to use their own sperm instead of using a donor when trying to conceive.

P. Jeremy Wang, a biologist at UPenn’s School of Veterinary Medicine, worked with his colleagues on the new paper published in Science Advances, which identified that SKP1-deficient spermatocytes show significantly reduced amounts of the maturing promoting factor (MPF) protein that triggers cell division.

Without SKP1, the spermatocytes cannot move into metaphase, which is the subsequent developmental phase in sperm cell creation.

Speaking on the pachytene phase, Wang said:

“This stage is really important, because the pair needs to be aligned for the exchange of genetic material between those two chromosomes. 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.”

Certain types of male infertility see men produce spermatogonia but not sperm, meaning they produce the typical immature cells that should develop into sperm cells, but these cells never actually become sperm.

Reproductive technologies like in vitro fertilization have made a huge difference for infertile patients, but the male needs to have at least some sperm. If the male has no sperm, then the only option is to use donor sperm.”

P. Jeremy Wang, UPenn's School of Veterinary Medicine

“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.”

The discoveries found in Wang’s work, which are the product of nearly a decade of research, could accelerate research into these particular conditions affecting male fertility, and further basic research on sperm development that is widely investigated in a number of other labs.

“Right now we use animals to do our research; we don’t have a cell culture system to produce sperm,” Wang said. “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 research team, led by postdoctoral researcher Yongjuan Guan, focused on SKP1 after screening for proteins in the area where paired chromosomes join during pachytene. Their knowledge that without SKP1 cells will inevitably die, whether they are sperm and egg cells or cells from throughout the body, led them to create a model system in mice that allowed them to turn off the protein in specific stages of cell life.

In order to better understand SKP1’s function, researchers turned off the protein’s action only in the germ cells and only in adult mice.

In mice, the pachytene phase lasts for six days. When SKP1 was turned off, the paired chromosomes separated much earlier than normal. Additionally, the introduction of a compound called okadaic acid to spermatogonia did not encourage the cells to enter the metaphase early as it usually would when SPK1 was missing.

Wang and his research team also conducted experiments in developing eggs. They found that SKP1 is also needed for women to produce viable eggs, as oocytes, the cells that progress to become mature eggs developed misaligned chromosomes and were often lost without SKP1 present.

Wang believes the study’s results “support a model where SKP1 functions as the long-sought intrinsic metaphase competence factor to orchestrate MI entry during male meiosis.”

On the future work this research will lead to, Wang said that “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.”

The research team aims to investigate further into the mechanisms by which SKP1 works to push cells into metaphase. Eventually, this work will hopefully lead to the discovery of strategies to address infertility and the development of novel laboratory techniques.