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

Hsiao Ying Kuo, Shih Yun Chen, Rui Chi Huang, Hiroshi Takahashi, Yen Hui Lee, Hao Yu Pang, Cheng Hsi Wu, Ann M. Graybiel*, Fu Chin Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 FOXP2R553H 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 FOXP2R553H 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.

Original languageEnglish
Pages (from-to)3542-3557
Number of pages16
JournalBrain
Volume146
Issue number8
DOIs
StatePublished - 1 Aug 2023

Keywords

  • basal ganglia
  • endosome trafficking
  • microtubule
  • striatum
  • vocalization

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