A recent study conducted jointly by MIT and National Yang Ming Chiao Tung University has provided valuable insights into the role of the gene Foxp2 in speech production and its connection to a speech disorder known as apraxia. The research was carried out on mice, and it revealed that mutations in the Foxp2 gene lead to disruptions in dendrites and neuronal synapses in the brain’s striatum, affecting movement control.
The mice with Foxp2 mutations showed difficulties in producing high-frequency sounds used for communication with other mice. These issues arise due to the faulty assembly of motor proteins, which are responsible for moving molecules within cells.
The lead authors of the study, Hsiao-Ying Kuo and Shih-Yun Chen of National Yang Ming Chiao Tung University, collaborated with Ann Graybiel, an MIT Institute Professor and a member of MIT’s McGovern Institute for Brain Research, on this research. The paper was published in the journal Brain on May 4.
This groundbreaking discovery sheds light on the underlying mechanisms of speech production and the impact of gene mutations on speech-related disorders, opening up new avenues for understanding and potentially treating apraxia and related conditions.
Speech control
Children with Foxp2-associated apraxia typically experience delayed speech development and have difficulties in articulating sounds, making their speech challenging to understand. The disorder is believed to result from impairments in brain regions like the striatum, responsible for controlling lip, mouth, and tongue movements. Interestingly, Foxp2 is also present in songbirds like zebra finches and is crucial for their song-learning abilities.
Foxp2 is a transcription factor, meaning it regulates the expression of many other genes. While this gene is found in various species, humans possess a distinct form of Foxp2. In a 2014 study, researchers demonstrated that mice expressing the human version of Foxp2 showed enhanced procedural learning, shifting from declarative to behavioral routines. These mice also exhibited longer dendrites in the striatum, linked to habit formation and motor control.
In their latest study, the scientists aimed to explore how the Foxp2 mutation associated with apraxia impacts speech production. They used ultrasonic vocalizations in mice as a proxy for speech, as rodents and other animals, like bats, utilize these vocalizations for communication.
Although previous studies hinted at Foxp2’s influence on dendrite growth and synapse formation, the underlying mechanism remained unknown. In this new study led by Liu, the researchers investigated the hypothesis that Foxp2 affects motor proteins, with the dynein protein complex being one such molecular motor responsible for shuttling molecules within cells, including neurons. These tiny molecules play crucial roles in the functioning of neurons by transporting substances along axons and within the cytoplasm.
A delicate balance
In the recent study, researchers identified dynactin1 as a crucial protein within the dynein complex, responsible for enabling dynein to move along microtubules. Foxp2, the transcription factor, plays a significant role in regulating dynactin1 production.
By focusing on the striatum, a region rich in Foxp2, the researchers observed that the mutated version of Foxp2 fails to suppress dynactin1 production properly. Consequently, cells produce an excess of dynactin1, disrupting the delicate dynein-dynactin1 balance and preventing the dynein motor from functioning effectively along microtubules.
This motor is essential for shuttling molecules required for dendrite growth and synapse formation. When these molecules remain trapped in the cell body, neurons cannot establish synapses, leading to a lack of proper electrophysiological signals necessary for speech production.
Mice with the Foxp2 mutation exhibited abnormal ultrasonic vocalizations, typically in the frequency range of 22 to 50 kilohertz. The researchers successfully reversed these vocalization impairments, along with deficits in molecular motor activity, dendritic growth, and electrophysiological activity, by reducing the expression of the gene encoding dynactin1.
Additionally, Foxp2 mutations have been associated with autism spectrum disorders and Huntington’s disease, as previously studied by Liu and Graybiel. Many other research groups are now exploring these mechanisms. Liu’s lab is also investigating the potential role of abnormal Foxp2 expression in the subthalamic nucleus of the brain, exploring its link to Parkinson’s disease.