Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c.
Cortico-basal ganglia circuits are critical for speech and language and are implicated in autism spectrum disorder, in which language function can be severely affected. We demonstrate that in the mouse striatum, the gene Foxp2 negatively interacts with the synapse suppressor gene Mef2c. We present causal evidence that Mef2c inhibition by Foxp2 in neonatal mouse striatum controls synaptogenesis of corticostriatal inputs and vocalization in neonates. Mef2c suppresses corticostriatal synapse formation and striatal spinogenesis, but can itself be repressed by Foxp2 through direct DNA binding. Foxp2 deletion de-represses Mef2c, and both intrastriatal and global decrease of Mef2c rescue vocalization and striatal spinogenesis defects of Foxp2-deletion mutants. These findings suggest that Foxp2-Mef2C signaling is critical to corticostriatal circuit formation. If found in humans, such signaling defects could contribute to a range of neurologic and neuropsychiatric disorders.
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Yi-Chuan
YC
Chen
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Hsiao-Ying
HY
Kuo
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Ulrich
U
Bornschein
Department of Neurology, National Hospital Organization, Tottori Medical Center, Tottori, Japan.
Hiroshi
H
Takahashi
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Shih-Yun
SY
Chen
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Kuan-Ming
KM
Lu
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Hao-Yu
HY
Yang
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Gui-May
GM
Chen
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Jing-Ruei
JR
Lin
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Yi-Hsin
YH
Lee
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Yun-Chia
YC
Chou
Neuroscience Program in Academia Sincia, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Sin-Jhong
SJ
Cheng
Neuroscience Program in Academia Sincia, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Cheng-Ting
CT
Chien
Anthropology and Human Genomics, Department Biology II, Ludwig-Maximilians University, Munich, Germany.
Wolfgang
W
Enard
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Wulf
W
Hevers
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Svante
S
Pääbo
McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Ann M
AM
Graybiel
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Fu-Chin
FC
Liu
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001479:Basal Ganglia / Q000378:metabolism; D003142:Communication; D003342:Corpus Striatum / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007858:Learning / Q000502:physiology; D064326:MEF2 Transcription Factors / Q000235:genetics; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014828:Vocalization, Animal / Q000502:physiology*
D051858:Forkhead Transcription Factors; C432918:Foxp2 protein, mouse; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D012097:Repressor Proteins