Frank Bradke’s work on neuronal polarization began in a bathroom. Though the toilet had been removed, the small room at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, was still recognizable as a former restroom, Bradke says. But that didn’t stop the budding neuro-scientist from setting up his new inverted microscope and spending about three years in the room, watching organelle movement in developing neurons.
“And he never had a complaint,” recalls his PhD advisor Carlos Dotti, now at the Katholieke Universiteit Leuven in Belgium. “He just cares about doing science. He can do experiments in the back yard, he wouldn’t care.”
METHOD: Bradke was interested in understanding why one of a developing neuron’s many small projections, called neurites, developed into the axon that would propagate action potentials down its length, while others would become dendrites, which would receive chemical signals from neighboring neurons. After many hours spent observing, he found that the neurite destined to become the axon accumulates more organelles,1 and its actin cytoskeleton is more dynamic.2
RESULTS: Upon accepting a postdoc in the lab of Marc Tessier-Lavigne at the University of California, San Francisco, and then at Stanford University, Bradke switched to studying axonal growth following injury. While the axons in the peripheral nervous system regenerate, neurons of the central nervous system, such as those of the spinal cord, do not. Even sensory neurons, which have axons both in the peripheral and central nervous systems, follow these basic rules—only the axon that projects into the periphery can regenerate. In the 1980s, however, researchers showed that by damaging the peripheral axon, it was possible to condition sensory neurons to later regenerate central nervous system axons as well—a phenomenon known as peripheral conditioning.
Bradke discovered that when he stimulated the cyclic AMP signaling pathway, damaged sensory neurons in the spinal cord could regenerate their axons, just like those conditioned with peripheral lesions.3 The finding, Bradke hopes, could have implications for the treatment of spinal cord injury. But there’s one major problem: for the cAMP treatment to be effective, it must be applied before injury takes place.
“Imagine you want to ride your motorbike, and then your partner tells you, ‘Ah, honey, don’t forget to have your cyclic AMP injection,’ ” Bradke says. “It wouldn’t make a lot of sense.”
DISCUSSION: In his own lab at the German Center for Neurodegenerative Diseases, Bradke continues to study axonal growth and regeneration. His group, formerly at the Max Planck Institute of Neurobiology, demonstrated the importance of microtubules, which essentially push through the actin cytoskeleton to form the developing axon.4 Stabilizing a neuron’s microtubules with a low dose of the chemotherapy drug taxol can prompt a cell to form multiple axons. Taxol also helps reduce the scarring on injured neurons, which can impede the regeneration process.
“We need to understand more about the molecular pathways involved in this process,” Bradke adds, “[and] also to see what is going on after spinal cord injury.”
“What we’re all interested in ultimately is how nerve cells behave in the more complex environment—either cells of the embryo or the injured nervous system,” agrees Tessier-Lavigne, now president of The Rockefeller University. And that’s “what he’s done beautifully in his own lab...tie together the cell biological work and the in vivo work.”
- F. Bradke, C.G. Dotti, “Neuronal polarity: Vectorial cytoplasmic flow precedes axon formation,” Neuron, 19:1175-86, 1997. (Cited 127 times)
- F. Bradke, C.G. Dotti, “The role of local actin instability in axon formation,” Science, 283:1931-34, 1999. (Cited 293 times)
- S. Neumann et al., “Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation,” Neuron, 34:885-93, 2002. (Cited 352 times)
- H. Witte et al., “Microtubule stabilization specifies initial neuronal polarization,” J Cell Biol, 180:619-32, 2008. (Cited 96 times)