Dozens of Genes That Block Regeneration of Neurons

Summary: Study identifies 40 genes in mice that actively suppress axon regeneration in the central nervous system.

Source: Yale

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.

In a massive screen of 400 mouse genes, Yale School of Medicine researchers have identified 40 genes actively involved in suppression of axon regeneration in central nervous system cells. By editing out one of those genes, they were able to restore axons in ocular nerves of mice damaged by glaucoma.

The findings are reported March 2 in the journal Cell Reports.

“This opens a new chapter in regeneration research,” said Stephen Strittmatter, the Vincent Coates Professor of Neurology and professor of neuroscience and senior author of the study.

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.

This shows the outline of a head against a blue background
By editing out one of those genes, they were able to restore axons in ocular nerves of mice damaged by glaucoma. Image is in the public domain

Among the 400 candidate genes the Yale team had previously identified in cultures of cortical neurons, they were able to show that one in 10 of those genes had direct in vivo impact on axon regeneration in central nervous system cells in mice. One of the 40 genes edited out encodes for an immune system regulator known as interleukin-22. Elimination of this immune mediator altered the expression of many neuronal regeneration genes and greatly increased axon regeneration in mouse models of glaucoma, they found.

Future research will explore how modifying or blocking those 40 genes might affect the repair of neurons damaged by stroke and traumatic brain and spinal cord injuries, Strittmatter said

Yale’s Jane Lindborg is lead author of the paper.

About this neurogenesis research news

Source: Yale
Contact: Bess Connolly – Yale
Image: The image is in the public domain

Original Research: Closed access.
Optic nerve regeneration screen identifies multiple genes restricting adult neural repair” by Jane Lindborg et al. Cell Reports


Optic nerve regeneration screen identifies multiple genes restricting adult neural repair


  • Candidate genes are screened for optic nerve regeneration effects by AAV-shRNA
  • Regeneration-limiting genes are confirmed by AAV CRISPR-Cas9 gene editing
  • Validated regeneration-limiting genes do not show axotomy-regulated expression
  • IL-22 loss activates both Stat3 and DLK, with upregulation of multiple pathways


Adult mammalian central nervous system (CNS) trauma interrupts neural networks and, because axonal regeneration is minimal, neurological deficits persist. Repair via axonal growth is limited by extracellular inhibitors and cell-autonomous factors. Based on results from a screen in vitro, we evaluate nearly 400 genes through a large-scale in vivo regeneration screen.

Suppression of 40 genes using viral-driven short hairpin RNAs (shRNAs) promotes retinal ganglion cell (RGC) axon regeneration after optic nerve crush (ONC), and most are validated by separate CRISPR-Cas9 editing experiments. Expression of these axon-regeneration-suppressing genes is not significantly altered by axotomy.

Among regeneration-limiting genes, loss of the interleukin 22 (IL-22) cytokine allows an early, yet transient, inflammatory response in the retina after injury. Reduced IL-22 drives concurrent activation of signal transducer and activator of transcription 3 (Stat3) and dual leucine zipper kinase (DLK) pathways and upregulation of multiple neuron-intrinsic regeneration-associated genes (RAGs). Including IL-22, our screen identifies dozens of genes that limit CNS regeneration.

Suppression of these genes in the context of axonal damage could support improved neural repair.

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