Missing molecule puts neurons off track

During fetal development, different types of neurons must journey to their proper place in the brain’s cerebral cortex. A wrong turn along the way may have devastating results, including periventricular heterotopia (PVH), a congenital brain malformation that can cause epilepsy, mental retardation and deficits in learning and memory.

PVH is associated with mutations in a gene known as Filamin-A, but little has been known about how these mutations cause neurons to go astray. Research led by Pasko Rakic, M.D., Ph.D., professor and chair of neurobiology and director of Yale’s Kavli Institute for Neuroscience, has now implicated MEKK4, an intracellular signaling molecule that contributes to proper neuronal migration.

In the December 7, 2006, issue of Neuron, Rakic’s team showed that MEKK4 regulates levels of Filamin-A protein in the developing brains of mice and that mice engineered to lack MEKK4 had impaired neuronal movement and an increased incidence of PVH.

The findings shed new light on PVH and on cortical development, “a dynamic and complex process that, in humans, occurs during gestation over many months and is regulated by numerous molecules,” says Rakic.