Using Roundworms to understand mechanisms underlying human infertility

April 1st 2022
Jeremy D. Bailoo

In a new study, researchers have discovered a previously unknown mechanism in roundworms that protects their egg cells from division errors. Uncovering and understanding this hidden mechanism could ultimately lead to new strategies for combating infertility in humans.

The diversity of animals is immense with ~30 major groups and thousands of sub-groups. According to geologic records, this diversity emerged around 500 million years ago during the Cambrian period and was typified by a period of massive speciation (the emergence of a large number of species). Humans and roundworms both belong to a group of animals that appeared around this time—bilaterians. Bilaterian animals are those which exhibit bilateral symmetry—where we can effectively cut an animal in half along a plane and have two symmetrical halves. Roundworms also have some reproductive similarities to humans—they engage in internal fertilization. Unlike humans where embryonic development occurs within the mother’s body (viviparous), roundworms lay eggs with embryonic development occurring outside the body within the egg (oviparous). Some roundworms, like C. elegans, are hermaphroditic, possessing both males and female reproductive organs making them ideal for the study of reproductive issues.

The roundworm, C. elegans. Credit: Zeynep F. Altun

For reproduction to be successful, in both humans and roundworms, an egg cell must divide perfectly. Egg cell divisions are so error-prone, however, that they are the leading cause of miscarriages and birth defects in humans. 

“Prior to our work [the current study], certain proteins were thought to be essential for cells to divide. However, when we removed these proteins, we were surprised to discover a previously hidden ‘backup’ mechanism that was able to kick in when the main proteins were missing. We uncovered something that other researchers missed because, if the major mechanism is in place, then you wouldn’t know that backup existed,” said Northwestern’s Sadie Wignall, who led the study—Gabriel Cavin-Meza, a graduate student in Wignall’s laboratory, is the paper’s first author.

When an egg is fertilized with sperm, the resulting embryo begins to rapidly divide, eventually developing into a healthy organism. If either the egg or the sperm have the wrong amount of genetic material, however, then the organism cannot properly develop. While other cells in the human body divide perfectly more than 99% of the time, egg cells are mysteriously error prone. About 10-25% of the time, egg cells incorrectly divide, resulting in the wrong amount of genetic material ending up in the embryo.

To understand why egg cells are more susceptible to errors, Wignall studies a football-shaped structure, called the spindle, which organizes genetic material before the egg divides.

Source

“The spindle is like a machine,” Wignall said. “It lines up chromosomes and then pulls them apart, ensuring that the right number of chromosomes end up in each half of the cell.”

The spindle is made up of long ropelike structures called microtubules. The microtubules gather into points at each pole of the spindle, giving it its football shape. Then microtubules attach to the chromosomes and eventually pull them apart.

“Motor proteins bind to the microtubules and take steps to move along them — just like humans walk using their legs,” Wignall said. “When microtubules are first formed, they are a random mess. Then the motors use this walking motion to push the microtubules around to arrange them into the spindle structure.”

Before Wignall’s new study, researchers believed two motor proteins (dynein and kinesin-12) were primarily responsible for this walking motion. But when Cavin-Meza removed both proteins from roundworms’ egg cells, he saw something shocking.

“When we removed these proteins, it made the entire spindle blow apart,” Wignall said. “Then we were surprised to see the spindle reform.”

In the absence of dynein and kinesin-12, another motor protein (called kinesin-5) came out of hiding to perform its backup duty. In the end, this previously unknown mechanism restored the spindle structure, allowing the chromosomes to be pulled apart.

Although this study was completed in C. elegans—a well-studied roundworm that is commonly used as a model for reproduction—Wignall believes similar mechanisms might be present in humans. But because so few human eggs cells are donated to science, researchers study model organisms to probe questions and work out details before examining humans.

“All of the components in our study are also present in human eggs,” Wignall said. “Spindles seem to form the same way in humans and even look exactly the same [emphases added]. It would be really interesting to see if humans also have this backup mechanism.”

This study was supported by the National Institutes of Health (award numbers R01GM124354 and T32 CA009560) and is a great example of how basic research using animals lays the foundation for insights into human health, diseases and associated processes.

Content adapted from the press release authored by Amanda Morris.

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