Caption:A new study shows that when the gene Foxp2 is knocked out in mouse striatal neurons (top right panel), the protein dynactin (stained red) and the chain that binds dynactin and dynein (stained green) show abnormal spacing compared to wildtype neurons (top left panel). This suggests that the functions of the motor complexes formed by these proteins may be impaired. The bottom panels show close-ups of the green and red labeled molecules.
Newswise — CAMBRIDGE, MA - A connection has been established between mutations in the gene Foxp2 and a speech condition known as apraxia, which makes the production of sound sequences challenging. A recent MIT and National Yang Ming Chiao Tung University investigation offers insight into how this gene governs speech production ability.
During a rodent investigation, the scientists discovered that Foxp2 mutations interfere with the creation of dendrites and neuronal synapses in the striatum region of the brain, which is crucial for movement regulation. Furthermore, mice with these mutations exhibited difficulties generating high-frequency sounds utilized for communication with other mice.
The scientists determined that Foxp2 mutations impede the appropriate arrangement of motor proteins, which transport molecules within cells, thereby causing these dysfunctions.
Ann Graybiel, an MIT Institute Professor, a member of MIT's McGovern Institute for Brain Research, and one of the paper's authors, stated, "These mice emit abnormal vocalizations, and the striatum shows numerous cellular abnormalities. This is a thrilling discovery. It is unexpected that a speech disorder might be caused by small motors within cells."
Fu-Chin Liu, who earned a PhD in 1991, is a professor at National Yang Ming Chiao Tung University in Taiwan and authored the study that is published today in the journal Brain. Liu collaborated with Graybiel on a 2016 study exploring the possible connection between Foxp2 and autism spectrum disorder. Hsiao-Ying Kuo and Shih-Yun Chen, both from National Yang Ming Chiao Tung University, are the primary authors of the new Brain paper.
Children who have Foxp2-associated apraxia typically have delayed speech development compared to their peers, and their speech is often challenging to comprehend. The condition is thought to result from difficulties in brain regions, like the striatum, that govern the coordination of lip, mouth, and tongue movements. Foxp2 is also present in the brains of songbirds, such as zebra finches, and plays an essential role in their ability to learn songs.
Foxp2 functions as a transcription factor, allowing it to regulate the expression of numerous target genes. While many species express Foxp2, humans possess a unique form of this gene. Graybiel and her colleagues conducted a study in 2014 that suggested the human variant of Foxp2, when introduced into mice, facilitated the transition from declarative to procedural types of learning.
The study conducted by the researchers demonstrated that mice that were genetically modified to express the human form of Foxp2, which differs from the mouse version by just two DNA base pairs, exhibited improved abilities to learn mazes and execute other tasks that involve converting repeated actions into behavioral routines. Additionally, the mice with the human-like Foxp2 showed longer dendrites - the slender extensions that help neurons form synapses - in the striatum, which plays a role in both habit formation and motor control.
The objective of the recent study was to investigate how the Foxp2 mutation, which has been associated with apraxia, impacts speech production, using ultrasonic vocalizations in mice as a substitute for speech. Several animals, including rodents and bats, generate these vocalizations to communicate with one another.
Previous research, including Liu and Graybiel's 2016 study, indicated that Foxp2 impacts dendrite growth and synapse formation, but the mechanism behind this phenomenon was not clear. In the recent study, spearheaded by Liu, the scientists explored one proposed mechanism, which suggests that Foxp2 impacts motor proteins.
One of the molecular motors impacted by Foxp2 is the dynein protein complex, which is a large collection of proteins that facilitates the transportation of molecules along microtubule scaffolds inside cells.
Graybiel explains that a diverse array of molecules is transported to various locations within our cells, including neurons, and this is made possible by an army of small molecules that transfer molecules within the cytoplasm or insert them into the membrane. In the case of neurons, these molecules may transport molecules from the cell body to the end of the axons.
A delicate balance
The dynein complex comprises various proteins, and the most crucial of these is dynactin1, a protein that interacts with microtubules and allows the dynein motor to travel along them. In the recent study, the scientists discovered that dynactin1 is among the primary targets of the Foxp2 transcription factor.
The researchers concentrated on the striatum, one of the regions where Foxp2 is commonly located, and demonstrated that the mutated variant of Foxp2 cannot inhibit dynactin1 production. As a result, cells generate excessive dynactin1. This disrupts the dynein-dynactin1 equilibrium, causing the dynein motor to become unable to move along microtubules.
The molecular motors are crucial for transporting molecules essential for dendrite growth and synapse formation on dendrites. When these molecules are trapped in the cell body, neurons are unable to form synapses necessary for generating the appropriate electrophysiological signals required for speech production.
In the study, the mice with the mutated Foxp2 had abnormal ultrasonic vocalizations with a frequency of around 22 to 50 kilohertz. The researchers were able to reverse these vocalization impairments and deficits in molecular motor activity, dendritic growth, and electrophysiological activity by reducing the expression of the gene that encodes dynactin1.
Aberrations in Foxp2 can also be a contributing factor to autism spectrum disorders and Huntington's disease, as previously examined in Liu and Graybiel's 2016 research and currently being studied by various other research teams. Furthermore, Liu's laboratory is researching the likelihood of an abnormal Foxp2 expression in the subthalamic nucleus of the brain as a potential element in Parkinson's disease.
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The research was funded by the Ministry of Science and Technology of Taiwan, the Ministry of Education of Taiwan, the U.S. National Institute of Mental Health, the Saks Kavanaugh Foundation, the Kristin R. Pressman and Jessica J. Pourian ’13 Fund, and Stephen and Anne Kott.
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