Impaired cognition, and in particular language, is a hallmark of common neuropsychiatric diseases such as autism and schizophrenia;however, the molecular mechanisms underlying higher cognitive function development and evolution in humans remain unknown. The elucidation of signaling pathways that are important for language and cognition will provide targets for future therapeutics. Frontal-striatal circuitry is critical for normal cognitive function and is frequently disrupted in neuropsychiatric disease. The transcription factor F0XP2 is the only gene currently identified that is mutated in patients with isolated language disturbances, and it has high expression in both frontal and striata) regions of developing human brain. Current data supports a role for both F0XP2 and its regulation of genes involved in autism and schizophrenia, The research in this proposal will focus on the developmentally regulated signaling pathways downstream of FbXP2 and how perturbations to these pathways result in cognitive defects in both ASD and schizophrenia, the specific aims include: 1) Identify the signaling pathways regulated by F0XP2 in human neurons, and which of these pathways are important for neuronal differentiation and/or maintenance, 2) Determine evolutionarily conserved and human-specific F0XP2 targets by conducting comparative whole gene transcriptome sequencing and F0XP2 promoter binding in fetal human, rhesus macaque, and mouse brain, and 3) Ascertain how Fdxp2 and Foxpl cooperatively regulate gene expression during CNS development by generating Foxpl conditional knockout mice and conducting genome wide Foxp2 promoter binding analysis.

Public Health Relevance

To Public Health Autism spectrum disorders and schizophrenia are two of the most common cognitive disorders in the United States and worldwide. Proper brain development is critical for cognition and these developmental processes are vulnerable to disruptions, which subsequently lead to mental illness. These proposed studies will provide insight into the developmental mechanisms underlying cognition and how they are disrupted in mental illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Transition Award (R00)
Project #
5R00MH090238-04
Application #
8444534
Study Section
Special Emphasis Panel (NSS)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2010-05-10
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$291,826
Indirect Cost
$76,706
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Usui, Noriyoshi; Co, Marissa; Harper, Matthew et al. (2017) Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development. Biol Psychiatry 81:220-230
Berto, Stefano; Usui, Noriyoshi; Konopka, Genevieve et al. (2016) ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism. Hum Mol Genet 25:2451-2464
Konopka, Genevieve; Roberts, Todd F (2016) Animal Models of Speech and Vocal Communication Deficits Associated With Psychiatric Disorders. Biol Psychiatry 79:53-61
Araujo, Daniel J; Anderson, Ashley G; Berto, Stefano et al. (2015) FoxP1 orchestration of ASD-relevant signaling pathways in the striatum. Genes Dev 29:2081-96
Wang, Guang-Zhong; Belgard, T Grant; Mao, Deng et al. (2015) Correspondence between Resting-State Activity and Brain Gene Expression. Neuron 88:659-66
Wang, Guang-Zhong; Hickey, Stephanie L; Shi, Lei et al. (2015) Cycling Transcriptional Networks Optimize Energy Utilization on a Genome Scale. Cell Rep 13:1868-80
Fontenot, Miles; Konopka, Genevieve (2014) Molecular networks and the evolution of human cognitive specializations. Curr Opin Genet Dev 29:52-9
Fogel, Brent L; Cho, Ellen; Wahnich, Amanda et al. (2014) Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2. Hum Mol Genet 23:4758-69
Usui, Noriyoshi; Co, Marissa; Konopka, Genevieve (2014) Decoding the molecular evolution of human cognition using comparative genomics. Brain Behav Evol 84:103-16
Lepp, Stephanie; Anderson, Ashley; Konopka, Genevieve (2013) Connecting signaling pathways underlying communication to ASD vulnerability. Int Rev Neurobiol 113:97-133

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