Genetic discovery offers clues for repairing damaged neural connections

A new discovery by neuroscientists at Brown University's Carney Institute for Brain Science challenges long-held beliefs in neurobiology about how neurons extend axons to reach their targets.

Published in PNAS, the findings provide what the authors call a "genetic atlas" of neuronal development as well as a potential step forward for understanding how to repair broken neural connections in conditions such as stroke and spinal cord injury.

"We discovered that during development, neurons turn on and off entire groups of genes that allow their axons to grow through different sections of their path," said study author Alexander Jaworski, an associate professor of brain science at the Carney Institute. "That's surprising." 

Axons are critical components of neural wiring. During embryonic development, they shoot out from neurons like plant tendrils searching for light, traveling along intricate and sometimes long pathways to reach target cells. For example, the axon of a motor neuron that enables foot movement extends all the way to the foot from the base of the spine.

How are axons capable of making these connections with such precision? Until now, the conventional thinking was that because axons are so long and respond so rapidly to their environment, the guidance about where to grow next must come from the axon tip. 

A team of researchers in Jaworski's lab discovered a new twist: Axons are actually controlled by a genetic switch in the cell body of the neuron.

Prior to this study, researchers knew that part of the secret to an axon's long-distance travel is that they stop at intermediate waystations en route to their destination. As they pass through a waystation, axons pivot as needed to aim for the next one - a process called axon pathfinding.

To understand this process in more depth, the researchers focused on commissural neurons, which connect the left and right sides of the central nervous system. This specific neuron type is particularly useful to study because its axon makes a distinct, sharp change in direction as it crosses the spinal cord midline.

Using a custom genetic tool, the team isolated commissural neurons in rodent cells at four different stages of development. They then analyzed gene expression using single-cell RNA sequencing. 

Their analysis revealed that as the axons passed through the midline waystation, the neurons shifted their gene expression - a type of genetic switch that triggered different guidance molecules to appear at the tip of the axon, allowing them to move from the midline to their next checkpoint.

Currently, researchers studying neural regeneration grapple with the same problem: They can make axons grow, but they can't get them to travel to the right place. This finding could help answer key questions about regrowing or repairing axons after damage from stroke or spinal injury, the researchers said. 

"Now that we know about this genetic switch in the neuron, we might be one step closer to finding a way to actually turn on the specific genes that allow axons to grow back to their correct targets," Jaworski said.

The team's work also uncovered gene expression data for more than 12,000 neurons across various developmental stages - far more than are involved in pathfinding. The result is a massive genetic atlas that could serve as a foundational resource for any scientist working to understand the spinal cord. 

The study has opened new doors for the team's trajectory, as well. 

"We're beginning to perceive the bigger picture of axon pathfinding, moving beyond the actions of individual molecules," Jaworski said. "How entire groups of genes collaborate to shape axon pathfinding decisions is an exciting research question the field doesn't yet fully understand."