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Complex wiring of the nervous system may rely on just a handful of genes and proteins

Sanford Consortium

Left: Axons of motor neurons as they make a pathfinding decision to reach and innervate specific muscle compartments in the limb of a mouse embryo.
Right: Motor neuron axons extending preferentially on alternating stripes of recombinant EphA, a growth-promoting signal for these cells.


Images courtesy of Dario Bonanomi, Salk Institute

Researchers in the lab of Sam Pfaff have discovered a startling feature of early brain development that helps explain how complex neuron wiring patterns are programmed using just a handful of critical genes. His team studied how motor neurons grow axons over the long distance from the spinal cord to muscles, a feature that is essential for creating the connections that allow the brain to control our movements. The growing motor neurons are tipped with a navigational device called the growth cone, which detects factors in the extracellular environment traversed by the neuron. The way that growth cones respond to their complex environment dictates where the neurons will grow and the connections the cells will form, but it has been a struggle to understand the molecular basis for growth cones' ability to detect minute differences in the concentration of factors in their environment. Pfaff's team discovered that motor neuron growth cones have "coincidence detectors" that cause a very strong growth response when two factors converge on the cell simultaneously, rather than sequentially.

"The budding neuron has to detect the local environment it is growing through and decide where it is and whether to grow straight, move to the left or right, or stop," says Pfaff. "It does this by mixing and matching just a handful of protein products to create complexes that tell a growing neuron which way to go."

The brain contains millions of times more neuron connections than the number of genes found in the DNA of brain cells. The Pfaff study is one of the first to try to understand how a growing neuron integrates many different pieces of information in order to navigate to its target and make a functional connection.

The findings might eventually shed new light on a number of clinical disorders related to faulty nerve cell functioning, such as ALS, also known as Lou Gehrig's disease, says Dario Bonanomi, a postdoctoral researcher in Pfaff's laboratory. They are also a jumping-off point for understanding defects that might arise during fetal development of the nervous system.

In addition, the researchers say the study, which was published in Cell, offers insights into cancer development, because a protein crucial to the "push and pull" signaling system, as well as other protein receptors described in the study, is also linked to cancer.