Vol 10. Issue 35 / November 15, 2010
Putting Down Roots: Franck Polleux Explores the Brain's Dynamic Beginnings
How do neurons move where they do? What tells ten billion sprouting cells to go, then stop, and drop roots – and thereby make a brain?
Such questions add up to one of the thorniest tasks in all of science, namely to discover what is the program that evolution has coded over eons for the self-assembly of this wondrous but complex device, the human brain – and in particular its most advanced and most human feature, the cerebral cortex?
The task of untangling this question is one that could discourage many a budding neuroscientist. Yet it is here, in the realm of cortical development, that Franck Polleux has enthusiastically set down his own roots. A cell biology professor at The Scripps Research Institute's Dorris Neuroscience Center, Polleux is drawn by the cortex's obvious importance, and the added challenge of studying its early growth spurt.
"During development, everything is moving," he says. "You can see cells and structures changing by the day or even by the hour. I would almost be bored to study things that weren't so dynamic."
The Roving Frenchman
Polleux was born a half mile above sea level, in the Alpine town of Gap, but spent most of his childhood in the heartland city of Lyon. As a boy, he read the French translation of Scientific American, as well as the French pop-sci monthly Science et Vie. Influential teachers nudged him, first towards biology, and then, as grad school loomed, towards neuroscience, the cortex, and finally the developing cortex. But the tools for investigating brain development were still quite basic. When the time came to start thinking about postdoctoral work, Polleux decided to find a lab that was working on the cutting edge – which brought him to America.
In 1996, at the Society for Neuroscience conference in San Diego, CA, he met a newly minted principal investigator from Johns Hopkins University named Anirvan Ghosh. The next year Polleux became Ghosh's very first postdoc.
"It was a very exciting and competitive time, and I was extremely lucky to be there," Polleux remembers.
Ghosh was a rising star in developmental neurobiology, as were Alex Kolodkin and David Ginty in the lab down the hall. With the latest molecular tools and reagents that were available in only a few labs, the scientists were developing powerful new assays and using them to make one discovery after another, particularly in the field known as axon guidance.
It was clear at the time that an axon – a neuron's output stalk – went where it did in response to ambient chemical cues. The task at hand was not only to identify these cues amid the dense molecular soup of an embryonic brain, but also to determine what the cues meant to different types of neurons, at different stages of development.
Polleux hit the ground running and soon achieved an extraordinary feat—his first two papers appeared in top journals, Science and Nature. His subject was Semaphorin 3A, part of a family of axon guidance proteins co-discovered a few years before by Kolodkin and Ginty. In the Science paper, Polleux reported that Semaphorin 3A specifically interacted with the Neuropilin-1 receptor on sprouting cortical neurons. It worked as a chemorepulsant to help keep these axons from straying out of bounds as they snaked their way to their neuronal targets.
Shortly thereafter, Polleux discovered that Semaphorin 3A had another function in the young cortex. Even as it repelled developing axons to keep them in line, it served as a chemoattractant for sprouting dendrites (dendros in greek means tree) – the root-like structures through which neurons receive most of their input signals. In the basic cortical unit known as the minicolumn, most neurons had a uniform alignment of their axons and dendrites, and it was now clear that Semaphorin 3A helped bring about this alignment.
When his postdoctoral fellowship was completed, Polleux went back to France – "like a good citizen," but also because he felt that his successes in America would translate into a first-rate research position back home.
He did get a coveted slot as a researcher with INSERM, France's NIH-like national biomedical science institute, and continued to publish high-profile research – in part through a continuing collaboration with Ghosh. But having spent three years in America, he expected more liberté as an investigator than French research culture was ready to provide. "It's not a system that's meant to give you independence when you start," he says. "You have to extend your domain of independence very slowly and painstakingly."
Migrating and Connecting
In the summer of 2002, Polleux returned to the United States and established his own lab at the University of North Carolina (UNC) at Chapel Hill. He continued studies related to neuronal migration, axon guidance, and dendrite development and put out several papers on Neurogenins – transcription factors that determine the identity and the migration pattern of neurons.
Other studies aimed to find the molecular triggers for axon formation. In a much-cited paper that appeared in the journal Cell in 2007, Polleux's lab reported that a kinase, LKB1, previously known as a tumor suppressor, is required for the sprouting of a cortical axon. "If you delete the gene encoding for LKB1, a cortical neuron is unable to form an axon, even though it can still migrate and even form dendrites," says Polleux.
In a study published last year, again in Cell, Polleux's lab discovered another basic mechanism that helps developing neurons find their way in the brain. A certain class of membrane-deforming proteins, known as the F-BAR domain, were known to be able to tubulate the membrane of a cell inward, thus helping to draw surface proteins inside. Polleux's group described an "inverse" F-BAR domain, on a neuronal protein known as srGAP2, that levers membranes outward. The action turns out to be crucial for the formation of "filopodia" – finger-like appendages that help a young neuron tug itself through the jungle of a developing brain and form anchorages – and also influences the sprouting of axons and dendrites.
"The importance of these srGAP genes is underscored by the fact that when they are mutated in humans, they cause a very severe mental retardation," Polleux says.
But one of the most commented-upon of his lab's studies so far is one that appeared in Neuron last year. The study focused on cortical interneurons, which somehow space themselves evenly in the mature cortex and appear to serve much as control rods do in a nuclear reactor. "They provide an essential inhibiting, moderating influence," explains Polleux. "If you disrupt their migration so that not enough reach the cortex, the pyramidal neurons in the cortex become hyperexcitable, which is one of the major causes of epilepsy, for example."
Polleux's group found that migrating interneurons respond one way to their ambient cues while beginning their journey, and in the opposite way after a certain interval. The ambient cues are the neurotransmitters GABA and glutamate, secreted by the interneurons and by ordinary pyramidal neurons, respectively.
"The effect of this relatively unusual signaling scheme," says Polleux, "might be to bring each interneuron into a region with a certain ratio of interneurons to pyramidal neurons – in other words, just where it needs to be."
In eight years at UNC, Polleux put out 20 research papers and reviews; received the Pew Scholar Award and two NARSAD Young Investigator awards; and was named a permanent member of the NIH study section that reviews grant applications in his field. And by 2010, he knew that it was time to make one more, perhaps final career move – to The Scripps Research Institute in La Jolla, where he arrived in late summer.
In his new lab at the institute's Dorris Neuroscience Center, Polleux and his lab members are following some of the clues uncovered in his earlier research. In one line of inquiry, they are characterizing the LKB1 axon-sprouting pathway and how it functions during and even after development. Many downstream targets of LKB1 turn out to be kinases that phosphorylate Tau1, a microtubule-binding protein that when hyper-phosphorylated is linked to neuronal degeneration in Alzheimer's and several other diseases.
"What started as basic developmental research on axon-sprouting could turn out to have broad implications for neurodegeneration," Polleux says.
His most ambitious project now – "almost pie in the sky," he calls it – is to find some of the mysterious genes that account for the huge cortical differences between humans and other primates. "We're doing some very exciting work now with srGAP2, which turns out to have undergone a very specific gene duplication event very recently and specifically in the human evolutionary lineage," he says.
When asked what else in his life, besides science, is worth noting, Polleux laughs – and offers, "Well, that I'm French?"
He makes no mention of hobbies or pastimes. "People who know me well understand that I'm an enthusiastic person generally, but especially about science. And you know, my area of research is also very tough and competitive: I really have to be driven by it."
Send comments to: mikaono[at]scripps.edu