Researchers ID 40 Genes that Thwart Axon Regeneration in CNS Cells

Researchers ID 40 Genes that Thwart Axon Regeneration in CNS Cells
System of neurons with glowing connections on black background

Researchers at the Yale School of Medicine report they have identified 40 genes that act to thwart the regeneration of cells in the central nervous system. When the researchers suppressed those genes in mouse models of glaucoma they were able to regenerate the damaged axons. The findings could eventually lead to developing therapies for patients of stroke, spinal cord damage, or traumatic brain injuries—avenues that don’t currently exists.

“This opens a new chapter in regeneration research,” said Stephen M. Strittmatter, M.D., Ph.D., the Vincent Coates professor of neurology at the Yale School of Medicine. To support this assertion, Strittmatter and colleagues presented their findings in an article (“Optic nerve regeneration screen identifies multiple genes restricting adult neural repair”) that appeared March 2 in Cell Reports.

“Based on results from a screen in vitro, we evaluated nearly 400 genes through a large-scale in vivo regeneration screen,” the article’s authors wrote. “Suppression of 40 genes using viral-driven short hairpin RNAs promotes retinal ganglion cell axon regeneration after optic nerve crush, and most are validated by separate CRISPR-Cas9 editing experiments.”

Strittmatter and colleagues found that suppression of the IL-22 gene altered the expression of many neuronal regeneration genes and greatly increased axon regeneration in mouse models of glaucoma.

“[Loss] of the IL-22 cytokine allows an early, yet transient, inflammatory response in the retina after injury,” the authors of the Cell Reports article detailed. “Reduced IL-22 drives concurrent activation of signal transducer and activator of transcription 3 and dual leucine zipper kinase pathways and upregulation of multiple neuron-intrinsic regeneration-associated genes.”

When central nervous system cells in the brain and spine are damaged by disease or injury, they fail to regenerate, limiting the body’s ability to recover. In contrast, peripheral nerve cells that serve most other areas of the body are more able to regenerate. Scientists for decades have searched for molecular clues as to why axons—the threadlike projections which allow communication between central nervous system cells—cannot repair themselves after stroke, spinal cord damage, or traumatic brain injuries.

Over the past several decades, Strittmatter and other scientists have found a handful of genes involved in suppressing regeneration of central nervous system cells. But the advent of RNAs to silence gene expression and new gene editing technologies capable of removing single genes and gauging their functional impact has allowed researchers to greatly expand their search for other culprits.

Future research will explore how modifying or blocking the 40 genes identified in the current study might affect the repair of neurons damaged by stroke and traumatic brain and spinal cord injuries, Strittmatter said. In addition, the Cell Reports article suggested that the multiple pathways uncovered by Strittmatter and colleagues could provide new molecular avenues to promote neural repair: “Importantly, the identification of multiple pathways provides the opportunity for multiplexed gene editing or combined pharmacological interventions.”