Then and Now: Frank Bradke Deciphers the Molecular Secrets of How Axons Grow

For years neurobiologist Frank Bradke has been fascinated by neurons, particularly why their ability to grow axons initially goes away after they become adult cells. “We want to understand how neurons grow during development,” said Bradke. “If we understand [that] well, then we can reactivate these mechanisms under pathological conditions to induce axons to regenerate.”

When The Scientist first spoke to Bradke 15 years ago, the neurobiologist had started his own lab at the German Center for Neurodegenerative Diseases to explore axonal growth and regeneration. His team showed, for instance, that microtubules are key to forming the developing axon.¹ More than a decade later, Bradke and his team have delved even deeper into axonal growth and regrowth, revealing new players in the process and even exploring approaches that may boost axonal regrowth after an injury.

Lessons from a Developing Axon

Axonal growth is the initial step of neuronal polarization, a process that gives neurons their classical shape and one that Bradke has studied for over two decades. During neuronal polarization, one of the multiple small projections coming out of the neuron’s cell body, known as neurites, stretches and becomes the axon; the others turn into branch-like dendrites.

Bradke’s early work showed that the cytoskeleton of the soon-to-be axon neurite is dynamic, exhibiting loose actin filaments that enable microtubules to protrude, elongate, and form the neuron’s axon.^1,2 The cytoskeleton dynamics helped Bradke understand the neuron’s inner metamorphosis that happens during axonal growth, yet he and his team wondered if they could recapitulate these processes in pathological conditions such as spinal cord injury, in which axons fail to regenerate.

For neurons to regrow, Bradke said, “You need to act on two processes: You have to gain the growth competence again and, at the same time, you need to reduce the scarring.” By using two anti-cancer drugs that also act as microtubule-stabilizing and anti-scarring agents, Bradke’s team showed they could stimulate axon regeneration, leading to improved motor function in an animal model of spinal cord injury.^3,4

While most of Bradke’s work has focused on the internal transformation neurons undergo to grow their axons, how non-neuronal cells and extracellular signals might influence axonal regeneration intrigued him as well.

To explore this question, his team zeroed in on the Ras homolog gene family member A (RhoA), an enzyme that regulates many intracellular processes and is known to relay inhibitory signals from the extracellular environment to the cytoskeleton.⁵ They found that after spinal cord injury, RhoA plays two opposing roles in neurons and astrocytes, a type of glial cell that contributes to central nervous system (CNS) regeneration. In neurons, RhoA’s actions lead to more compact actin filaments that block microtubule protrusion and prevent axonal regrowth. In astrocytes, on the other hand, RhoA activation stimulates pathways that boost axon regeneration.⁶

While these findings may help explain why early attempts to use Rho inhibitors in patients with acute spinal cord injury were unsuccessful, Bradke stressed that they also highlight how researchers should consider the potential impact of therapies on other cell types in the CNS.⁷ “You also [have to] start to think more about the nervous system as an ecosystem,” he added.

Axonal Growth and Regeneration: The Journey Goes On

As Bradke and his team’s quest to understand axonal growth continues, he is turning his attention to other aspects of the process that have fascinated him for years, including how the other neurites that do not develop into an axon know that one of them has started that transformation.

The researchers are also testing whether anticonvulsant medications, such as pregabalin, which Bradke’s team showed can enhance axonal regeneration, could be beneficial in more severe spinal cord injuries or even potentiate the effects of rehabilitation. They have started to explore this line of inquiry by showing how a microtubule-stabilizing drug affects rehabilitation and enhances locomotor recovery in animals with moderate spinal cord injuries.^8,9

While Bradke’s fascination with the dynamic changes during neuronal development has motivated him to keep investigating new questions, he recognizes the contributions that young researchers have made to his work. “I often see myself more like a soccer coach,” Bradke explained. “I [have been] very fortunate that the people that I have in the lab are extremely good players. They have wonderful dribbling; they shoot very nice goals. That really brought the lab forward.”