Gene in autism hotspot regulates neuronal migration | Domain

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

Mice that lost part of chromosome 16 linked to autism had impaired neuronal movement during embryonic development and decreased cortex size, which is new. study offers. But enhancing the expression of only one of the missing genes, TAOK2It can restore typical brain cell migration in animals.

TAOK2 is one of 29 genes on a segment of chromosome 16 called . 16p11.2. People missing in this area often have enlarged heads and developmental delays, and about 30 percent have autism. People with mutations in one copy of TAOK2 may also have features of autism.

In the field, the big question was whether we could narrow down all these genes [on 16p11.2] To a few may 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 is interesting, she adds, to associate TAOK2 with a specific phenotype.

TAOK2 encodes two protein variants, or isoforms: alpha and beta. Beta aids in the formation of neurons dendritic spinesaccording to a previous report study from the same group.

The alpha version of TAOK2 controls neuronal migration, according to new work. The researchers introduced autism-related mutations to impaired alpha or beta isoforms in mice before birth. After four days, analysis of brain tissue samples revealed cell repositioning only in the cortices of the alpha transgenic animals.

A network of brain scans comparing mice with different genetic variants.

head space: Mice lacking the 16p11.2 region show a similar brain anatomy to mice that only lost TAOK2. They share fewer similarities with their KCTD13-deficient colleagues.

“TAOK2 is implicated in various aspects of neural development,” says the lead researcher. Froilan Calderon de Anda, Head of the Neuronal Development Research Group at the University Medical Center Hamburg-Eppendorf in Germany. “Depending on the isoform, you will get different effects.”

The two isoforms add a touch of plot to the story, he says Santosh GirirajanD., assistant professor of biochemistry and molecular biology at Penn State in University Park, Pennsylvania, who was not involved in the study. “It’s like watching a movie where you think there’s one person, but it’s actually a twin.”

eThe enhanced expression of both wedge forms showed that only alpha binds to microtubules, which are components of the cell’s internal scaffolding 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 active transcript of JNK1.

Defective neuronal migration may be one reason why people with 16p11.2 deletion syndrome have a thinner cerebral cortex, says study investigator. Melanie Richter, a postdoctoral researcher in D’Anda’s lab. “Cells end up in the wrong layer and don’t connect to the right targets.” These cells aren’t active enough, Richter says, and they end up dying as a result.

The team compared mice deficient in TAOK2 with animals that had lost one copy of 16p11.2 and found similar migration defects, which were normalized by showing TAOK2 alpha expression.

MRI also revealed similarities in brain anatomy, including cortical size, between the two models. 16p11.2 deletion mice share less similarity with mice lacking KCTD13another gene associated with autism is 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.

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

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

Neuronal migration and cortex size are only 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 dissect the roles of the TAOK2 isoforms. Unpublished data from the group indicate that TAOK2 beta regulates protein production in neurons.

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

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