Gene in autism hotspot regulates neuronal migration | Spectrum | Autism research news

misled: Neurons lacking TAOK2 are misplaced in the mouse cortex.

Mice missing a portion of chromosome 16 linked to autism have impaired neuronal movement during embryonic development and reduced cortical volume, a new study shows. But increasing expression of just one of the missing genes, TAOK2, can restore typical brain cell migration in the animals.

TAOK2 is one of 29 genes on a segment of chromosome 16 called 16p11.2. People who lack this region often have an enlarged head and developmental delay, and about 30 percent also have autism. People with mutations in one copy of TAOK2 can also have autistic traits.

“In the field, a big question was whether we can narrow down all of these genes [on 16p11.2] to some who could contribute [autism]says Smita Yadav, an assistant professor of pharmacology at the University of Washington in Seattle, who was not involved in the work. It’s exciting to associate TAOK2 with a specific phenotype, she adds.

TAOK2 encodes two protein variants, or isoforms: alpha and beta. Beta helps form a neuron’s dendritic spines, according to a previous study by the same group.

The alpha version of TAOK2 controls neuronal migration, according to the new work. The researchers introduced autism-associated mutations to affect either the alpha or beta isoform in prenatal mice. Four days later, analysis of brain tissue samples revealed altered cell positioning only in the cerebral cortices of alpha-mutant animals.

“TAOK2 is involved in various aspects of neuronal development,” says lead researcher Froylan Calderón de Anda, head of the Neural Development Research Group at the University Medical Center Hamburg-Eppendorf in Germany. “You get different effects depending on the isoform.”

The two isoforms add a plot twist to the story, says Santhosh Girirajan, an assistant professor of biochemistry and molecular biology at Pennsylvania State University in University Park, Pennsylvania, who was not involved with the study. “It’s like watching a movie where you think there’s only one person, but they’re actually twins.”

EThe improved expression of both isoforms revealed that only alpha binds to microtubules, components of a cell’s internal framework that are essential for its movement. JNK1, an enzyme that stabilizes microtubules, was less active in TAOK2-deficient mice, while neuronal migration resumed after the introduction of an activated version of JNK1.

Faulty neuronal migration could be one reason people with 16p11.2 deletion syndrome have a thinner cerebral cortex, says study researcher Melanie Richter, a postdoctoral fellow in de Anda’s lab. “The cells end up in the wrong layer and don’t connect to the right targets.” These cells aren’t active enough, says Richter, and will eventually die.

The team compared the TAOK2-deficient mice to animals lacking one copy of 16p11.2 and found similar migratory defects that were normalized by increasing expression of TAOK2 alpha.

MRI also showed similarities in brain anatomy, including cortex volume, between the two models. The 16p11.2 deletion mice bore less resemblance to mice lacking KCTD13, another autism-related gene in the same 16p chromosomal region.

The results were published on September 19 in Molecular Psychiatry.

fast lane: A fluorescent protein shows altered microtubule dynamics in mice lacking TAOK2 alpha.

The results suggest that TAOK2 is a major player in 16p11.2-associated autism and an important therapeutic target, says Richter. “It’s really the only known contribution to the 16p-associated phenotype,” she adds.

However, neuronal migration and cortex size are just two aspects of the 16p phenotype, Girirajan says, noting that other genes in the 16p region likely contribute to other aspects of the phenotype.

The team continues to analyze the roles of the TAOK2 isoforms. Unpublished data from the group suggest that TAOK2 beta regulates protein production in neurons.

“Now we’re trying to take a more general approach, using a protein synthesis inhibitor in prenatal animals to see if we can change their behavioral problems,” says de Anda.