Neuroscientists discover complex genetic programs behind our movements

A UNIGE team has discovered the genetic programs that allow motor neurons to retract from the spinal cord. This discovery opens up prospects for combating neurodegeneration.

The motor cortex is made up of neurons that are responsible for muscle contraction. These neurons have cellular extensions called axons, which project from the cortex to the spinal cord. During brain development, some of these neurons retract their axons to project, not into the spinal cord, but into the brain. How does this happen?

Neuroscientists from the University of Geneva (UNIGE) have discovered that everything is linked to genetic programming. Indeed, our genes define which parts of the cortex are dedicated to motor functions and which are not, by directing neuronal projections. This fundamental discovery, published in the journal Natureopens up new avenues for countering motor disorders.

The cerebral cortex is the outer part of the brain responsible for higher cognitive functions, such as thinking, perception, decision-making, language, and memory. It also processes sensory information and controls movement.

To do this, it devotes part of its volume to movement: the motor cortex. This is where the neurons responsible for muscle contraction, the corticospinal neurons, project to the spinal cord. Despite the compartmentalization of the cortex, the corticospinal neurons are located outside the motor cortex. Why?

Selection during development

To answer this question, neuroscientists focused on mice. “Currently available technologies do not allow us to address these questions in humans. Corticospinal neurons are highly conserved from one species to another and can therefore be studied in rodents,” explains Denis Jabaudon, full professor in the Department of Fundamental Neurosciences at the UNIGE Faculty of Medicine and initiator of the study.

Using approaches that make brain tissue transparent and allow neuron subtypes to be specifically stained, the research team first studied the evolution of corticospinal projections during brain development. “We have thus confirmed a fascinating observation made several decades ago, but little known to neuroscientists,” explains Professor Jabaudon.

Early in brain development, neurons in the cortex project into the spinal cord. Those that will form the future motor cortex remain there, while those that will form the rest of the cortex gradually retract. Eventually, in an adult brain, some corticospinal neurons can act all the way to the spinal cord, and others with a smaller range of action, which remain in the brain itself.

A dedicated genetic program

Jabaudon’s team then compared the genes expressed by these two types of neurons and identified a family of genes responsible for their ability to retract. “Without them, these neurons would remain anchored in the spinal cord during development, and our cortex would probably be deprived of its higher cognitive functions,” Jabaudon adds.

To demonstrate the importance of this genetic program, the researchers focused on three genes and, using gene editing techniques – CRISPR-Cas9 – were able to modulate their expression in neurons with projections in the spinal cord.

“This is a major technical challenge and a new way to assess the influence of a set of genes on cellular mechanisms,” explains Jabaudon. It was thus possible to force the retraction of neurons from the spinal cord to the brain.

An essential discovery

“It is important to understand how corticospinal neurons emerge during development and how they project into our central nervous system, because they are essential for fine motor skills. However, they are very sensitive to spinal cord injuries or the consequences of amyotrophic lateral sclerosis, a disease that causes progressive paralysis of the muscles,” explains Professor Jabaudon.

“In this study, we managed to force neurons to retract. But there is every reason to believe that the opposite could also be done, which opens up fascinating possibilities,” he adds. The research team is now considering reprogramming neuronal cells in other contexts, such as neurodegenerative diseases.