Mid-Atlantic Consortium Newsletter Summer 2013

CNMC Researchers Gain Insight into Neural Development

Doublecortin deficient neuron

The pink dots represent cargos building up in neurons deficient in the protein doublecortin.

Normal Neuron

A normal neuron.

Working in the laboratory, researchers at Children’s National Medical Center (CNMC) have identified how a mutation in the gene doublecortin (DCX) results in a severe developmental disorder called lissencephaly. They found the protein doublecortin (Dcx), encoded by the gene, to be essential for the proper function of Kif1a, a motor protein that transports substances responsible for neuron development, growth, and signaling.

Their findings, published in September in the journal Molecular Cell, could pave the way to better understanding of epilepsy and other related disorders.

In the developing brain, nerve cells, or neurons, must migrate from the areas where they originated to areas where they will settle into their proper role. This neuronal migration, which occurs as early as the second month of gestation in humans, is controlled by a complex assortment of chemical guides and signals. When these signals are absent or incorrect, neurons do not end up where they belong, resulting in structurally abnormal or missing areas of the brain.

Judy Liu, M.D., Ph.D., an assistant professor of pediatrics at CNMC, has been studying Dcx, which is expressed by immature neurons during brain development. Dcx is called a microtubule-associated protein because it binds to microscopic cylindrical filaments responsible for cell structure, transport of materials within the cells and other processes. Importantly, Dcx is required for the normal migration of neurons into the cerebral cortex, the outer layer of the brain responsible for learning and memory.

Mutations in Dcx disrupt neuronal migration, causing lissencephaly, or “smooth brain,” which is associated with seizures and intellectual disability. There are no available treatments for this rare brain formation disorder; children born with the condition are severely neurologically impaired and often die within several months of birth.

Dcx mutations had been hypothesized to regulate molecular motors like Kif1a “but no one had found an instance where that happens,” Liu says.

In a series of laboratory tests in mice, Liu’s team observed that neurons deficient in Dcx and Dclk1 (a structurally similar protein that has the same function as Dcx) had significantly less Kif1a in their cell bodies than regular neurons. They also saw significantly fewer “cargos” leaving the cell bodies in Dcx- and Dcx/Dclk1-deficient neurons, and found that disease-associated Dcx mutations disrupted the function of Kif1a.

“Basically what we found is an entirely new mechanism regulating neural development,” Liu says. “Dcx changes how molecular motors behave.”

Normally, Dcx interacts with one component of a neuron-specific protein to make sure cargos get where they need to go within cells, Liu says. Mutations to Dcx severely disrupt the transport function, so it barely works; cargos build up in the cell body.

“These cells are still in the developmental phase, so if the cargos can’t move, the cells can’t grow and connect to other neurons,” says Liu. “That’s probably what results in seizures and intellectual disability.”

The findings provide a potential new target for therapies for lissencephaly, Liu says.

Liu and colleagues are now looking into which of the 45 known microtubule motors specifically are regulated by Dcx. They also want to further investigate other proteins structurally similar to Dcx. Three other Dcx proteins are associated with human disease, and a causative gene for dyslexia is structurally very similar to Dcx.

“By studying rare diseases, we sometimes gain insight into more commonly-occurring disorders that share the same biological and molecular processes,” Liu says, “For example, studying lissencephaly offers a way for us to study epilepsy.”


For more information on Liu’s work, see www.lablife.org/lab?groupid=2492.

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