Science1 publisher2 min readPublished
Whole gene cohorts switch in the cell body as axons reach the spinal midline
Brown University researchers sequenced more than 12,000 rodent commissural neurons at four developmental stages and found the cell body swapping guidance receptor programs as axons reached the spinal midline. The profiling stops short of manipulating those genes.
The Scientist · Science desk
What happened
- Researchers at Brown University's Carney Institute report in PNAS that a genetic program running in the neuron's cell body directs axon pathfinding at waystations along the route.
- They ran single-cell RNA sequencing on rodent commissural neurons sampled at four developmental stages, comparing transcriptional profiles across those phases.
- Cells that had reached the spinal midline showed a shift in nuclear gene expression that changed which guidance receptors and signalling molecules were sent out to the axon tip.
- The standard view in neurobiology had held for decades that all of an axon's directional decisions were made locally, at the growing tip, because the distances involved are long and the environment changes fast.
- The profiles cover more than 12,000 neurons, which the authors offer as a resource for work on regrowing and re-steering tracts after spinal cord trauma or stroke.
Compiled by The ScientistSomething wrong?How this is made
Why it matters
- capability Groups working on tract repair get candidate guidance genes indexed to where the axon is along its path, so an intervention can be timed to a checkpoint instead of applied uniformly to the whole route.
- constraint Every profile here comes from an embryonic rodent cord, so anyone reaching for a human application first has to show an injured adult neuron can be made to run a developmental program.
- decision The next spend is on perturbation rather than more sequencing, because an expression atlas cannot say which members of a cohort are required for the turn.
The switch this paper describes keeps the growth cone supplied. On the team's account, the shift in the cell body changes which guidance receptors and signalling molecules get sent out to the axon tip, after which the axon leaves the midline for its next waypoint [4]. Local steering and a central schedule are compatible on exactly that description, because the tip still reads the cues around it, using whatever receptors the soma has supplied.
Much of what the study can claim comes down to the design. Cells came from rodent commissural neurons at four developmental stages, pulled out with a custom genetic isolation tool [2][3]. Single-cell sequencing gives one snapshot per cell, and the cells sequenced before the midline are not the cells sequenced after it, so the order of events is inferred from stage. Brown University's summary describes profiling and does not report an experiment that switched a cohort on or off to see whether the axon changed course [16]. Commissural neurons suit the question: they connect the left and right halves of the central nervous system and turn sharply just as they cross the midline [13].
More than 12,000 individual neurons went into the atlas [1]. Split evenly across the four stages, that is about 3,000 cells per stage [14]. Sample sizes like that are ample for seeing groups of genes move together, which is what the team reported [4]. How much each member of a group matters is a separate question.
"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 Alexander Jaworski, an author of the study and an associate professor of brain science at the Carney Institute [9][12]. "That's surprising," he said [10].
Jaworski put the therapeutic case with a hedge of his own. "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," he said [11].
The gap he is pointing at is between growth and aim. Bioengineering can already coax severed axons to sprout and extend after injury, and getting them back to the right synaptic partners has stayed the hard part [8]. A parts list indexed to position along the route speaks to that problem. But these were embryonic neurons in a normally developing rodent spinal cord [2], and an adult neuron at an injury site is not in that state. Whether it can be pushed to run the embryonic program is a separate experiment.
What to watch
- A perturbation test: force the post-midline gene cohort on early and see whether axons leave the midline sooner or aim wrong.
- Whether adult injured neurons, in rodents first, can be pushed into the embryonic expression state the atlas describes.
- Release of the full 12,000-cell dataset in a form other labs can query for candidate guidance receptors.