The researchers found that these malfunctions occur because Foxp2 mutations prevent the proper assembly of motor proteins that move molecules inside cells.
“These mice have abnormal vocalizations and a lot of cellular abnormalities in the striatum,” says Ann Graybiel, MIT professor, member of MIT’s McGovern Institute for Brain Research, and author of the paper. “This was an exciting finding. Who would have thought that speech problems could arise 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 collaborated in 2016 to investigate the potential link between Foxp2 and autism spectrum disorder. The lead authors of the new Brain paper are Hsiao-Ying Kuo and Shih-Yun Chen of National Yang Ming Chiao Tung University.
The disease is believed to be caused by disorders in brain regions 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 that means it can control the expression of many other target genes. Many species express Foxp2, but humans have a specific form of Foxp2. In a 2014 study, Graybiel and colleagues found evidence that when the human form of Foxp2 was expressed in mice, it allowed mice to switch from declarative learning to procedural 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 better at learning mazes and performing other tasks that require translating repetitive movements into behavioral patterns. Mice with human-like Foxp2 also had longer dendrites—thin extensions that help neurons make synapses—in the striatum, which is involved in habit formation and motor control.
Although 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, Foxp2’s effects on motor proteins.
One of these molecular motors is the dynein protein complex, a large group of proteins responsible for moving molecules along microtubule scaffolds inside cells.
“All kinds of molecules are shuttled to different places in our cells, and that’s certainly the case with neurons,” says Graybiel. “There is an army of small molecules that move molecules around the cytoplasm or anchor them to the membrane. In a neuron, they can send molecules from the cell body to 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 Foxp2 transcription factor.
The researchers focused on the striatum, one of the regions where Foxp2 is most abundant, and showed that a mutated version of Foxp2 was unable to suppress dynactin1 production. Without this brake in place, cells overproduce dynactin1. This disrupts the delicate balance of dynein-dynactin1, which prevents the dynein motor from moving along microtubules.
These motors are necessary to transport molecules necessary for dendrite growth and synapse formation in dendrites. With these molecules trapped in the cell body, neurons cannot form synapses to generate the electrophysiological signals necessary to make speech production possible.
Mice with a mutated version of Foxp2 typically had abnormal ultrasound sounds with a frequency of 22-50 kHz. The researchers showed that by knocking down the gene encoding dynactin, they could reverse these vocal impairments and deficits in molecular motor activity, dendritic growth, and electrophysiological activity.
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 that many other research groups are now investigating. 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.