piRNA Molecules Protect Germ Cells From Damage
Passing one's genes on to the next generation is a mark of evolutionary success. So the body works to ensure that next generation genes are exact replicas of the originals
Biologists at the University of Pennsylvania School of Veterinary Medicine have identified one way the body creates exact duplicates. This protective role is filled by a class of small RNA molecules called pachytene piwi-interacting RNAs, or piRNAs.
Without piRNAs, germ-cell development in male
mice comes to a halt. Because piRNAs play such
an important role in allowing sperm to develop,
defects to piRNAs or defects within molecules
piRNAs interact with may be responsible for
some cases of male infertility.
Jeremy Wang, an associate professor of developmental biology and director of the Center for Animal Transgenesis and Germ Cell Research at Pennsylvania School of Veterinary Medicine, and Ke Zheng, a postdoctoral researcher in Wang's lab, authored the study, which appears in PLOS Genetics.
Scientists know of 8 million different piRNAs
in existence they are the most abundant
type of small non-coding RNA.
The piRNA molecule is so named because it forms
complexes with piwi proteins. Earlier research
indicates that piwi-piRNA complexes suppress
the activity of transposable elements
stretches of DNA that can change position
and cause potentially damaging genetic effects.
Jumping gene sequences are also known as transposons.
Wang: "There are about 50 human diseases caused
by transposable elements, so it's important for the
body to have a way to repress them."
Transposon-suppressing activity had already been confirmed in a group of piRNAs called pre-pachytene piRNAs. Pre-pachytene piRNAs are expressed before meiosis, or germ cell division. But Zheng and Wang also wanted to know if piRNAs that emerge during meiosis, called pachytene piRNAs, were also able to silence transposons.
Working in male mice, researchers isolated an enzyme called MOV10L1, known to interact with piwi proteins and believed to help produce piRNA molecules. In the mutant mice they created, researchers were able to selectively inactivate MOV10L1 during and after meiosis.
Mice created without MOV10L1 functioning before or during meiosis, were sterile. When Zheng and Wang examined their sperm cells more closely, they found that spermatogenesis had stopped following meiosis. Although early stages or spermatids, were present, there were no mature sperm.
Zheng and Wang continued experimenting to pinpoint the critical role MOV10L1 played at the pachytene stage or during meiosis. They discovered that although MOV10L1 mutants lack pachytene piRNAs, their pre-pachytene piRNAs levels were unaffected, however, the mutation apparently "turned on" after spermatogenesis had initiated, and only early-stage sperm had resulted. Furthermore, the spermatids all had severe DNA damage.
In MOV10L1 mutants, piwi proteins congregate together with mitochondria, suggesting that mitochondria are involved in the generation/organization of pachytene piRNAs.
Researchers suspect that the DNA damage may have been caused by transposons free to act in the absence of piRNAs. And they have found a build-up of pachytene piRNA precursors in the testes of the mutants. A finding that raises the possibility of another mechanism by which damage occurs.
"It could be the accumulation of precursor molecules is causing some of the damage," Wang said.
This newly identified function of MOV10L1, playing an essential role in producing pachytene piRNAs, gives research a greater understanding of germ-cell development.
Wang: "This is the first time we've shown that pachtyene piRNA is required for maintaining genome integrity in the post-meiotic germ cells. It turns out that MOV10L1 is a master regulator of the piRNA pathway and is required for the production of all piRNAs, both pre-pachytene and pachytene."
Any disruptions to this "master regulator," therefore, can lead to problems.
"I think we're just beginning to appreciate the significance of this pathway," Wang continued. "Mutations at various points in the pathway could lead to infertility."
This research was supported by the National Institutes of Health's National Institute of Child Health and Human Development.
Original article: http://www.upenn.edu/pennnews/news/class-rna-molecules-protects-germ-cells-damage-penn-vet-researchers-show