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New research shows the brain protein srGAP2 can impose cell shape by directly bending membranes and forming filopodia to control the migration and branching of neurons during brain development, says senior study investigator Franck Polleux. (Credit: Nicolas Rougier)

UNC CHAPEL HILL (US)—A critical gene has been identified in determining if the brain will develop normally.

Researchers at the University of North Carolina at Chapel Hill have discovered that establishing the neural wiring necessary for the brain to function normally depends on the ability of neurons to make finger-like projections of their membrane called filopodia.

In laying down the neural circuitry of the developing brain, billions of neurons must first migrate to their correct destinations and then form complex synaptic connections with their new neighbors. When the process goes awry, neurodevelopmental disorders, such as mental retardation, dyslexia, or autism may result.

Scientists had thought that the only way for a cell to morph and move is through the action of the cytoskeleton or the scaffold inside the cell, pushing membrane forward or sucking it in.

But new research shows the brain protein srGAP2 can also impose cell shape by directly bending membranes and forming filopodia to control the migration and branching of neurons during brain development, says senior study investigator Franck Polleux, associate professor of pharmacology.

Because srGAP2 is one of a family of proteins that have been implicated in a severe mental retardation syndrome called the 3p- syndrome, the new research could also yield important insights into the underlying causes of this and other forms of mental retardation, researchers say.

Polleux and his colleagues began looking at srGAP2 because the gene was almost exclusively “turned on” or expressed during brain development. The brain protein contains a unique combination of domains, small functional chunks of protein sequence that may be common to other proteins as well. The star of these domains is one called the F-BAR domain, one of a handful of similarly termed “BAR domains” that have recently become a hotbed of research.

Working with slices of mouse brain, the UNC researchers used electrical current to introduce pieces of genetic material that would either ramp up or, conversely, knock down the action of the protein’s F-BAR domain. They then cultured brain slices in petri dishes to watch how the neurons behaved ’in the wild’ in their native environment.

When the researchers ramped up the activity of the domain, they saw that the neurons formed the finger-like filopodia which blocked migration by inducing too many branches.

“The textbook notion is that F-BAR proteins fold inward, but here we show it can do the opposite” explains Polleux. “This is a completely novel mechanism for producing filopodia.”

The neurons migrated at a faster rate and branched less when researchers reduced the expression of the protein.  Under a microscope, neurons move like little inchworms. In front, the long thin cellular protrusion of the neuron extends, pauses, then drags the bulbous cell body behind it, then extends again, and so on.

Polleux says the F-BAR domain of srGAP2 appears to tightly control the amount of branching neurons undergo so they can be more streamlined when they need to migrate, and branch when they need to establish connections with other neurons.

Because disruptions in these critical connections would have detrimental effects on brain development, the next step is to  determine whether mutations in the srGAP2 gene are involved in autism or in other forms of mental retardation in addition to the 3p- syndrome, Polleux says.

His laboratory is also interested in determining the function of approximately 25 other genes containing F-BAR-like domains, many of which are expressed in the developing brain.

Funding for the study, which was published as the cover story of the Sept. 4 issue of the journal Cell, came from the National Institutes of Health and the Pew Charitable Trusts.

University of North Carolina at Chapel Hill news: http://uncnews.unc.edu/