New pathway implicated in axon regrowth

By Naveed Saleh, MD, MS
Published April 23, 2018

Key Takeaways

While performing large-scale genetic screening in the roundworm Caenorhabditis elegans, researchers discovered a new pathway—the PIWI-interacting small RNA (piRNA) pathway—that plays a role in nerve regeneration, according to a recent article in Neuron.

“For us this finding is totally unexpected,” said lead author Kyung Won Kim, PhD, University of California San Diego School of Medicine, La Jolla, CA. “We are now investigating detailed mechanisms that regulate the pathway to inhibit axon regeneration, including identifying specifically which piRNA elements are involved and how they function in axon regrowth.”

Experts previously thought that the piRNA pathway functioned only in the germline—as a defense mechanism vs transposable elements—however, there is new evidence that it acts on somatic cells, too.

The researchers noticed enhanced axon regrowth in posterior lateral microtubule (PLM) mechanosensory neurons in homozygous C. elegans mutants that lacked PRDE-1, TOFU-3, and PRG-1, as well as in mutants lacking TOFU-5, TOFU-7, EKL-1, DRH-3, and EGO-1. The researchers used a femtosecond laser instrument to precisely cut axons.

Importantly, tested mutants had normal body size and growth rates; thus, this observed outcome was not attributable to enhanced growth.

Using smFISH analysis, the researchers found that prde-1 transcripts are located in neurons. Furthermore, the piRNA pathway inhibits axon regrowth independent of nuclear transcriptional silencing. They found, however, that piRNA pathway is dependent on the slicer domain of PRG-1/PIWI, which suggests that post-transcriptional silencing plays a role.

The researchers write that the piRNA pathway inhibits axonal regeneration in C. elegans is based on the following four factors:

“First, loss of function in select genes of the piRNA pathway results in enhanced axon regrowth, independent of piRNA-mediated nuclear silencing. Second, two essential piRNA factors, PRDE-1 and PRG-1/PIWI, act in a cell-autonomous and gonad-independent manner to inhibit axonal regrowth after injury. Third, prde-1 and prg-1 transcripts are expressed in multiple somatic cells including neurons. Fourth, the slicer domain of PRG-1/PIWI is required for its inhibitory effect on axon regrowth.”

The researchers at first believed that their findings were unlikely, but after further testing, their findings proved unquestionable.

“This came as a total surprise. piRNA wasn’t anywhere on our radar, but now we are convinced that it is a new pathway that functions in neurons and, with some work, could offer therapeutic targets for helping neurons do better against injury,” said study author Yishi Jin, PhD, chair, Section of Neurobiology, Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine.

The researchers expressed hope that this finding will someday help damaged neurons become stronger and regrow in people who sustain traumatic injury, such as spinal cord damage, sports accidents, motor vehicle accidents, and stroke.

This research was supported by the National Institutes of Health, an American Heart Association postdoctoral fellowship and a Canadian Institutes of Health Research Postdoctoral Fellowship.

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