Scientists in the U.S. have found that many of the genes that are involved in repairing spinal cord damage in an ancient species of fish are also active in the peripheral nervous system of mammals. The findings hint that it may one day be possible to harness the same genes to help repair nerve damage in humans.  

The researchers, led by scientists at the Marine Biological Laboratory (MBL) of the Eugene Bell Center for Regenerative Biology and Tissue Engineering, and the Feinstein Institute for Medical Research, used RNA-Seq to track changes in the transcriptional profiles of lamprey fish spinal cords and brains following spinal cord injury (SCI). “We found a large overlap with the hub of transcription factors that are driving regeneration in the mammalian peripheral nervous system,” says Jennifer Morgan, Ph.D., director of the MBL's Eugene Bell Center for Regenerative Biology and Tissue Engineering. Morgan is co-author of the researchers' study, published today in Scientific Reports, and entitled “Highly Conserved Molecular Pathways, Including Wnt Signaling, Promote Functional Recovery from Spinal Cord Injury in Lampreys.”

Unlike mammals, which can only readily regenerate the peripheral nervous system after injury, some fish such lampreys, as well as amphibians and reptiles, can also spontaneously regenerate following spinal cord injury.  Lampreys, for example, can recover from a completely severed spinal cord and regain the ability to swim, without any form of therapy. “They can go from paralysis to full swimming behaviors in 10 to 12 weeks,” Morgan states.


 


 

Lampreys swimming in a tank at the Marine Biological Laboratory, Woods Hole. MBL scientist Jennifer Morgan and colleagues use lamprey as a model system to study spinal cord regeneration. These lampreys are four to five years old and are still considered to be in the larval stage. [Amanda R. Martinez]


Lampreys are a jawless, eel-like fish that diverged from their common ancestor with humans about 550 million years ago, the authors explain. What hasn’t been understood to date is which molecular pathways are involved that allow spinal cord regeneration to occur. “Scientists have known for many years that the lamprey achieves spontaneous recovery from spinal cord injury, but we have not known the molecular recipe that accompanies and supports this remarkable capacity,” says Ona Bloom, Ph.D., at the Feinstein Institute for Medical Research and the Zucker School of Medicine at Hofstra/Northwell.

Despite the evolutionary distance between humans and lampreys, recent sequencing of the lamprey genome has shown that that the animal demonstrates “molecular pathways that are conserved with mammals, including genes related to axon guidance and regeneration, synaptic transmission, neural patterning and neurodegeneration.” The organization of the lamprey central nervous system (CNS) is also highly analogous to human and other jawed vertebrates, the authors note. 

To try and identify the molecular pathways that support functional recovery following spinal cord injury in lampreys, the team followed changes in gene transcription throughout the time course of spinal cord regeneration in fish with completely severed spinal cords. The researchers carried out transciptional profiling of samples taken from the brains and spinal cords of the lampreys at multiple time points, starting within hours after injury, until healing was complete three months later.

The results showed that the expression of many genes in the spinal cord changed over time as spinal cord regeneration progressed, and even at the very last stages of recovery there were many differentially expressed genes in the spinal cords of injured compared with uninjured lampreys. Of particular interest, and “somewhat surprisingly,” the team found that there were complex transcriptional changes in the brain, as well as in the spinal cord. “One of the most surprising findings from this study is the robust and complex transcriptional responses occurring in the lamprey brain after SCI,” they write. Even at the point of full regeneration 12 weeks after the initial injury, there were 238 newly differentially expressed transcripts in the spinal cord, and 88 newly differentially expressed transcripts in the brain, respectively. “Thus, dynamic changes in gene expression persist throughout the time course of recovery after SCI, even at late stages of behavioral recovery.” 

This finding “reinforces the idea that the brain changes a lot after a spinal cord injury,” says Morgan. “Most people are thinking, 'What can you do to treat the spinal cord itself?' But our data really support the idea that there's also a lot going on in the brain.”

About 3% of the transcripts that were differentially expressed during spinal cord regeneration belonged to Wnt pathways. “These included members of the Wnt and Frizzled gene families, and genes involved in downstream signaling,” the authors write. There are 19 mammalian Wnt genes, and many are conserved across species. Wnt pathways are involved in multiple biological processes that could play a role in SCI, “including body plan patterning, contact-dependent signaling, cell proliferation, tissue development and regeneration, stem cell self renewal, and axon guidance,” the authors comment. Previous studies have also shown that Wnt genes promote regeneration in zebrafish and after tail injury in salamanders.

Interestingly, the MBI and Feinstein team found that treating spinal cord–injured lampreys using an inhibitor of Wnt signaling stopped the animals from regaining full locomotor function. “…when we treated the animals with a drug that inhibits the Wnt signaling pathway, the animals never recovered their ability to swim,” says Morgan. 

The authors acknowledge that new research will be needed “to determine the mechanism by which Wnt signaling promotes functional recovery, including an analysis of the affected cellular and molecular pathways.”

One of the key findings of the study was that spinal cord injury in lampreys induces the expression of many transcripts that are associated with regeneration in the mammalian peripheral nervous system, and this highlights what the team calls “the power of this organism as a model for identifying and studying highly conserved, fundamental, pro-regenerative molecular pathways.”

“In this study, we have determined all the genes that change during the time course of recovery and now that we have that information, we can use it to test if specific pathways are actually essential to the process,” Bloom says.






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