In the developing brain, special proteins that act like molecular tugboats push or pull on growing nerve cells, or neurons, helping them navigate to their assigned places amidst the brain's wiring.
How a single protein can exert both a push and a pull force to nudge a neuron in the desired direction is a longstanding mystery that has now been solved by scientists from Dana-Farber Cancer Institute and collaborators in Europe and China.
Jia-huai Wang, PhD, who led the work at Dana-Farber and Peking University in Beijing, is a corresponding author of a report published in the August 7 online edition of Neuron that explains how one guidance protein, netrin-1, can either attract or repel a brain cell to steer it along its course. Wang and co-authors at the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, used X-ray crystallography to reveal the three-dimensional atomic structure of netrin-1 as it bound to a docking molecule, called DCC, on the axon of a neuron. The axon is the long, thin extension of a neuron that connects to other neurons or to muscle cells.
As connections between neurons are established in the developing brain and throughout life axons grow out from a neuron and extend through the brain until they reach the neuron they are connecting to. To choose its path, a growing axon senses and reacts to different molecules it encounters along the way. One of these molecules, netrin-1, posed an interesting puzzle: an axon can be both attracted to and repelled from this cue. The axon's behavior is determined by two types of receptors on its tip: DCC drives attraction, while UNC5 in combination with DCC drives repulsion.
"How netrin works at the molecular level has long been a puzzle in neuroscience field," said Wang, "We now provide structure evidences that reveal a novel mechanism of this important guidance cue molecule." The structure showed that netrin-1 binds not to one, but to two DCC molecu
|Contact: Teresa M Herbert|
Dana-Farber Cancer Institute