Mutations in the Foxp2 gene have been linked to apraxia, a speech disorder that makes it difficult to produce sound sequences. A recent study from National Yang Ming Chiao Tung University and MIT sheds light on how this gene regulates voice production.
Researchers found that Foxp2 mutations disrupt the development of dendrites and neuronal connections in the brain’s striatum, which is key to regulating movement. The high-frequency sounds that mice use to communicate with each other were also less effective in animals with these changes.
Mutations in Foxp2 prevent motor proteins from being assembled correctly, leading to these defects, the researchers found.
“These mice have abnormal vocalizations and there are many cellular abnormalities in the striatum,” says Ann Graybiel, an MIT professor, member of the McGovern Institute for Brain Research at MIT, and an author of the paper. “
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 lead author of the study, which appears today in the journal Brain. Liu and Graybiel also collaborated on a 2016 study on the potential link between Foxp2 and autism spectrum disorder.
Children with Foxp2-linked apraxia tend to start speaking later than other children, and their speech is often difficult to understand. The disorder is thought to arise from damage to areas of the brain, such as the striatum, which control movements of the lips, mouth and tongue. Foxp2 is also expressed in the brains of songbirds, such as zebra finches, and is critical for these birds’ ability to learn songs.
Foxp2 encodes a transcription factor, which means 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 his colleagues found evidence that the human form of Foxp2, when expressed in mice, allowed the mice to accelerate the transition from declarative to procedural types of learning.
In this 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 turning repeated actions into behavioral routines.
Mice with human-like Foxp2 also had longer dendrites—slender extensions that help neurons form synapses—in the striatum, which is involved in habit formation as well as motor control.
In the new study, the researchers wanted to investigate how the Foxp2 mutation, which has been linked to apraxia, affects speech production, using ultrasound 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, 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 one proposed mechanism, which is that Foxp2 affects motor proteins.
“All kinds of molecules move to different places in our cells, and that’s certainly true for neurons,” Graybiel says. “There is an army of small molecules that move molecules around in the cytoplasm or insert them into the membrane.” In a neuron, they can send molecules from the cell body all the way down the axons.”
The dynein complex consists of several other proteins. The most important of these is a protein called dynactin1, which interacts with microtubules and allows 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 transcription factor Foxp2.
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