Speech- and language-linked FOXP2 mutation targets protein motors in striatal neurons

Kuo et al. identify a mechanism by which the KE family mutation in FOXP2 may give rise to childhood apraxia of speech. Using a mouse model, they show that the mutation disrupts the formation of striatal circuits required for vocalization - ultrasonic in mice and speech in humans - by inhibiting intracellular trafficking. Human speech and language are among the most complex motor and cognitive abilities. The discovery of a mutation in the transcription factor FOXP2 in KE family members with speech disturbances has been a landmark example of the genetic control of vocal communication in humans. Cellular mechanisms underlying this control have remained unclear. By leveraging FOXP2 mutation/deletion mouse models, we found that the KE family FOXP2(R553H) mutation directly disables intracellular dynein-dynactin 'protein motors' in the striatum by induction of a disruptive high level of dynactin1 that impairs TrkB endosome trafficking, microtubule dynamics, dendritic outgrowth and electrophysiological activity in striatal neurons alongside vocalization deficits. Dynactin1 knockdown in mice carrying FOXP2(R553H) mutations rescued these cellular abnormalities and improved vocalization. We suggest that FOXP2 controls vocal circuit formation by regulating protein motor homeostasis in striatal neurons, and that its disruption could contribute to the pathophysiology of FOXP2 mutation/deletion-associated speech disorders.

Automated summary

Kuo et al. have identified a mechanism by which the KE family mutation in FOXP2 can lead to childhood apraxia of speech. Using a mouse model, they found that the mutation disrupts the formation of vocalization circuits by inhibiting intracellular trafficking. This discovery sheds light on the genetic control of vocal communication in humans and could contribute to understanding speech disorders associated with FOXP2 mutations.