A gene in the autism hotspot regulates neuronal migration | Spectrum | Autism Research News

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Diverted from the right path: Neurons lacking TAOK2 are misplaced in the mouse cortex.

Mice missing a piece of autism-linked chromosome 16 have impaired neural movement during embryonic development and reduced cortical volume, a new study has found. But boosting the expression of just one of the missing genes, TAOK2, can restore typical brain cell migration in animals.

TAOK2 is one of 29 genes in a segment of chromosome 16 called 16p11.2. People missing this region often have an enlarged head and developmental delay, and around 30% also have autism. People with mutations in one copy of TAOK2 may also have autistic traits.

“In the field, a big question has been whether we can reduce all these genes [on 16p11.2] to a few who could contribute to [autism]“Says Smita Yadav, assistant professor of pharmacology at the University of Washington in Seattle, who was not involved in the work. It’s exciting to connect TAOK2 to a particular 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-linked mutations to alter the alpha or beta isoform in prenatal mice. Four days later, analysis of brain tissue samples revealed altered cell positioning in the cortex of alpha-mutated animals only.

Grid of brain scans comparing mice with different genetic alterations.

Head space: Mice lacking the entire 16p11.2 region show brain anatomy similar to mice lacking only TAOK2. They share fewer similarities with their KCTD13-deficient littermates.

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

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

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

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

The team compared TAOK2-deficient mice with animals lacking one copy of 16p11.2 and found similar migration defects, which were normalized by increasing TAOK2 alpha expression.

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

The results were published on September 19 in Molecular psychiatry.

Fluorescent protein reveals altered microtubule dynamics in mice lacking TAOK2 alpha.

Expressway: Fluorescent protein reveals altered microtubule dynamics in mice lacking TAOK2 alpha.

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

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

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

“We are now trying to take a more general approach by using a protein synthesis inhibitor in prenatal animals to see if we can modify their behavioral problems,” says de Anda.

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