Research with Mice Yields Important Discoveries About Pregnancy, Birth, and Reproduction

Reproduction is life’s most basic function, and in some ways also its most mysterious. Researchers working with mice and rats have made several recent reproduction-related breakthroughs, including an in vivo cure for infertility in mice, creating rat sperm from stem cells, discovering that a previously disregarded type of estrogen actually plays a crucial role in the development of offspring, creating male-only or female-only mouse litters, and the birth of a healthy baby mouse from an unfertilized egg.

Gene Therapy Cures Infertility in Mice

Infertility is a heartbreaking and little-understood condition with many potential causes. Now, one type of infertility has been cured, at least in mice.

In a study at Kyoto University, scientists were able to restore fertility in mice that had been rendered infertile through ovary cell-targeting mutations.

In healthy ovaries, developing oocytes are supplied with nutrients and necessary hormones by granulosa cells. In the study, mice were bred to have unexpressed Kitl genes, which impaired the function of the granulosa cells.

After a virus-based gene therapy with a functional copy of the Kitl gene was injected into their ovaries, granulosa function was restored in 80% of the infertile mice. Those mice mated naturally and gave birth to normal offspring, though the female offspring were still infertile.

Researchers say the approach could someday lead to new infertility treatments for humans.

The Important Role of a “Weak” Estrogen

A type of estrogen called estriol, one of three common estrogens present in very low levels in women before they conceive, has taken on new importance thanks to recent research at Yale University.

When a woman becomes pregnant, her levels of estriol increase dramatically, but scientists never knew why or what the hormone does. This so-called “weak estrogen” was previously thought to have no function, but that couldn’t be further from the truth.

In fact, Yale researchers have discovered that estriol plays a crucial role. To determine its role in reproduction, the researchers treated pregnant mice with estriol. The estriol-treated mice showed improvements in pregnancy rate, litter size, pregnancy success, and uterus structure.

And the improvements also extended to their offspring, which showed less anxiety and greater exploratory behavior. When the baby mice reached adulthood, they showed permanent changes in gene expression.

If the findings are applicable and the process found to be safe in humans, women could be given estriol to make pregnancies safer and less susceptible to complications.

Scientists Generate Primordial Germ Cells in Rats

A team of Japanese researchers has produced healthy, fertile rat offspring with sperm made from stem cells. This is only the second species in which scientists have been able to generate primordial germ cells (the precursors of sperm and eggs) from embryonic stem cells. The breakthrough was first made with mice in 2011, but the process has not been repeated in any other animal since.

After inducing epiblast-like cells from rat embryonic stem cells, then inducing primordial germ cells from the epiblast cells, scientists injected the primordial germ cells into rat testes. The cells developed into mature sperm, which was injected into rat oocytes and resulted in healthy and fertile offspring. The rats were not able to produce offspring through normal mating, however.

Scientists speculate that although the 10-year gap between the success of the process in mice and rats indicates it may take years to replicate in any other animal species, much less humans, it does hold promise.

Scientists could use the new technology to assist reproduction in animals nearing extinction, and to better understand infertility in humans. It could also have positive implications for other research, since rats are genetically closer to humans than mice, and some diseases can only be modeled in rats.

“Virgin” Birth from Unfertilized Eggs

In a scientific first, researchers at Shanghai Jiao Tong University were able to cause a female mouse to give birth to a baby mouse that grew from an unfertilized egg.

Parthenogenesis, or asexual reproduction, occurs in other species, including worms, bees, aphids, Komodo dragons, and some sharks, but this is the first time it has been induced in a mammal.

The researchers used CRISPR, the gene-editing tool, to change the chemical tags on seven imprinted gene regions of the mouse genome, making it seem like the mother’s genetic code came from a male.

They did this for 220 unfertilized mouse eggs, and successfully transferred around 194 of the resulting embryos into 14 female mice. Three mice were born and one lived to adulthood and was able to reproduce normally, though it was about 20% smaller than the average mouse.

The new study may help scientists study congenital diseases caused by genomic imprinting, such as Prader-Willi syndrome, Beckwith-Wiedemann syndrome, and Angelman syndrome.

Single-Gender Litters in Mice

In addition to generating litters with no male input, scientists at the Francis Crick Institute and the University of Kent have been able to use gene editing to create all-male and all-female litters of mice.

To control the gender of the mice in a litter, the researchers used CRISPR to genetically inactivate the embryos of the undesired sex shortly after fertilization, allowing only the desired sex to develop.

Not only was the method 100% effective, it did not lead to a 50% reduction in the size of the litter. On average, single-sex litters were between 61% and 72% the size of a normal litter. The offspring showed no harmful effects from the method.

The team targeted the Top1 gene, which is common in many mammals, so the method may work with other animals, though further research is required to determine if the method is safe.

The discovery could be useful in research and agriculture, which often requires animals of a specific sex. Being able to generate single-sex litters of animal offspring could reduce or eliminate the culling of the animals of the unrequired sex.

As is the case with many scientific breakthroughs, when it comes to reproduction, rodents are once again leading the way. Thanks to the work of animal researchers around the world, we may have more answers about how reproduction works, the causes of infertility, and methods of making the experience safer and more successful.