Mutations in a gene called Foxp2 have been linked to a type of speech disorder called apraxia that makes it difficult to produce sound sequences. A new study from MIT and National Yang Ming Chiao Tung University sheds light on how this gene controls the ability to produce speech.
In a mouse study, the researchers found that mutations in Foxp2 disrupt the formation of neural dendrites and synapses in the brain’s striatum, which play important roles in movement control. Mice with these mutations also showed impairments in their ability to produce the high-frequency sounds they use to communicate with other mice.
Those dysfunctions arise because Foxp2 mutations prevent the proper assembly of motor proteins, which move molecules inside cells, the researchers found.
“These mice have abnormal vocalizations, and in the striatum there are a lot of cell abnormalities,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and an author on the paper. “This was an exciting finding. Who would have thought that a speech problem could come from tiny motors inside cells?”
Fu-Chin Liu PhD ’91, a professor at National Yang Ming Chiao Tung University in Taiwan, is the lead author of the study, which appears today in the journal Brain. Liu and Graybiel also worked together on a 2016 study on the potential link between Foxp2 and autism spectrum disorder. The main authors of the new Brain role are Hsiao-Ying Kuo and Shih-Yun Chen from National Yang Ming Chiao Tung University.
voice control
Children with Foxp2-associated apraxia tend to start speaking later than other children, and their speech is often difficult to understand. The disorder is thought to arise from deficiencies in regions of the brain, such as the striatum, that control movements of the lips, mouth, and tongue. Foxp2 is also expressed in the brains of songbirds such as zebra finches and is critical to those birds’ ability to learn songs.
Foxp2 encodes a transcription factor, which means that it can control the expression of many other target genes. Many species express Foxp2, but humans have a special form of Foxp2. In a 2014 study, Graybiel and colleagues found evidence that the human form of Foxp2, when expressed in mice, allowed them to speed up the switch from declarative to procedural types of learning.
In that study, the researchers showed that mice engineered to express the human version of Foxp2, which differs from the mouse version by only two DNA base pairs, were much better at learning mazes and performing other tasks that require converting repeated actions. in behavioral routines. Mice with human-like Foxp2 also had longer dendrites, the thin extensions that help neurons form synapses, in the striatum, which is involved in habit formation and motor control.
In the new study, the researchers wanted to explore how the Foxp2 mutation that has been linked to apraxia affects speech production, using ultrasonic vocalizations in mice as a proxy for speech. Many rodents and other animals, such as bats, produce these vocalizations to communicate with each other.
While previous studies, including work by Liu and Graybiel in 2016, had suggested that Foxp2 affects dendrite growth and synapse formation, the mechanism by which this occurs was unknown. In the new study, led by Liu, the researchers investigated a proposed mechanism, which is that Foxp2 affects motor proteins.
One of these molecular motors is the dynein protein complex, a large group of proteins that is responsible for transporting molecules along microtubule scaffolds within cells.
“All sorts of molecules stray to different places in our cells, and that’s certainly true of neurons,” says Graybiel. “There is an army of tiny molecules that move molecules around in the cytoplasm or place them on the membrane. In a neuron, they can send molecules from the cell body to the axons.”
a delicate balance
The dynein complex is made up of several other proteins. The most important of these is a protein called dynactin1, which interacts with microtubules, allowing the dynein motor to move along the microtubules. In the new study, the researchers found that dynactin1 is one of the main targets of the Foxp2 transcription factor.
The researchers focused on the striatum, one of the regions where Foxp2 is most frequently found, and showed that the mutated version of Foxp2 cannot suppress dynactin1 production. Without this brake, the cells generate too much dynactin1. This upsets the delicate balance of dynein-dinactin1, which prevents the dynein motor from moving along the microtubules.
Those motors are needed to transport molecules that are necessary for the growth of the dendrites and the formation of synapses on the dendrites. With those molecules stranded in the cell body, neurons are unable to form synapses to generate the proper electrophysiological signals they need to make speech production possible.
Mice with the mutated version of Foxp2 had abnormal ultrasonic vocalizations, which typically have a frequency of around 22 to 50 kilohertz. The researchers showed that they could reverse these vocalization disturbances and deficits in molecular motor activity, dendritic growth, and electrophysiological activity by knocking down the gene encoding dynactin1.
Foxp2 mutations may also contribute to autism spectrum disorders and Huntington’s disease, through mechanisms that Liu and Graybiel previously studied in their 2016 paper and are now being explored by many other research groups. Liu’s lab is also investigating the potential role of abnormal Foxp2 expression in the brain’s subthalamic nucleus as a possible factor in Parkinson’s disease.
The research was funded by the Taiwan Ministry of Science and Technology, the Taiwan Ministry of Education, the US National Institute of Mental Health, the Saks Kavanaugh Foundation, the Kristin R. Pressman and Jessica J. Pourian Fund’ 13 and Stephen and Anne Kott.
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