FoxP1 orchestration of ASD-relevant signaling pathways in the striatum.
Mutations in the transcription factor Forkhead box p1 (FOXP1) are causative for neurodevelopmental disorders such as autism. However, the function of FOXP1 within the brain remains largely uncharacterized. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and patient-relevant heterozygous Foxp1 mouse brains. We demonstrate a role for FoxP1 in the transcriptional regulation of autism-related pathways as well as genes involved in neuronal activity. We show that Foxp1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations. Finally, we demonstrate that FoxP1 has an evolutionarily conserved role in regulating pathways involved in striatal neuron identity through gene expression studies in human neural progenitors with altered FOXP1 levels. These data support an integral role for FoxP1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatal pathways important for vocal communication.
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Daniel J
DJ
Araujo
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Ashley G
AG
Anderson
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Stefano
S
Berto
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Wesley
W
Runnels
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Matthew
M
Harper
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Simon
S
Ammanuel
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
Michael A
MA
Rieger
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Department of Biology, Jackson State University, Jackson, Mississippi 39217, USA;
Hung-Chung
HC
Huang
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Kacey
K
Rajkovich
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Kristofer W
KW
Loerwald
University of Texas at Austin, Section of Molecular Genetics and Microbiology, Austin, Texas 78712, USA.
Joseph D
JD
Dekker
University of Texas at Austin, Section of Molecular Genetics and Microbiology, Austin, Texas 78712, USA.
Haley O
HO
Tucker
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
Joseph D
JD
Dougherty
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Jay R
JR
Gibson
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Genevieve
G
Konopka
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D057895:Haploinsufficiency; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009474:Neurons / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D014705:Verbal Behavior / Q000502:physiology
C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D012097:Repressor Proteins
autism; gene expression; neuronal activity; striatum; ultrasonic vocalizations