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Modeling the functional genomics of autism using human neurons.

Molecular psychiatry | 2012

Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and to model some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After 4 weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASDs) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis, we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. As NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD.

Pubmed ID: 21647150 RIS Download

Research resources used in this publication

None found

Antibodies used in this publication

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Associated grants

  • Agency: NIMH NIH HHS, United States
    Id: R01 MH094714
  • Agency: NICHD NIH HHS, United States
    Id: N01-HD-4-3383
  • Agency: NIMH NIH HHS, United States
    Id: R01MH081754
  • Agency: NIMH NIH HHS, United States
    Id: K99 MH090238
  • Agency: NIMH NIH HHS, United States
    Id: R37 MH060233
  • Agency: NIMH NIH HHS, United States
    Id: R00 MH090238
  • Agency: NIMH NIH HHS, United States
    Id: R01 MH081754
  • Agency: NIMH NIH HHS, United States
    Id: K08MH074362
  • Agency: NIMH NIH HHS, United States
    Id: R37MH060233
  • Agency: NIMH NIH HHS, United States
    Id: K99MH090238
  • Agency: NIMH NIH HHS, United States
    Id: K08 MH074362
  • Agency: NIMH NIH HHS, United States
    Id: K08 MH074362-05
  • Agency: NICHD NIH HHS, United States
    Id: N01-HD-4-3368

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Allen Institute for Brain Science (tool)

RRID:SCR_006491

Seattle based independent, nonprofit medical research organization dedicated to accelerating the understanding of how human brain works. Provides free data and tools to researchers and educators and variety of unique online public resources for exploring the nervous system. Integrates gene expression data and neuroanatomy, along with data search and viewing tools, these resources are openly accessible via the Allen Brain Atlas data portal. Provides Allen Mouse Brain, Allen Spinal Cord Atlas, Allen Developing Mouse Brain Atlas, Allen Human Brain Atlas,Allen Mouse Brain Connectivity Atlas, Allen Cell Type Database, The Ivy Glioblastoma Atlas Project (Ivy GAP), The BrainSpan Atlas of the Developing Human Brain.

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RRID:SCR_007303

Functional genomics data repository supporting MIAME-compliant data submissions. Includes microarray-based experiments measuring the abundance of mRNA, genomic DNA, and protein molecules, as well as non-array-based technologies such as serial analysis of gene expression (SAGE) and mass spectrometry proteomic technology. Array- and sequence-based data are accepted. Collection of curated gene expression DataSets, as well as original Series and Platform records. The database can be searched using keywords, organism, DataSet type and authors. DataSet records contain additional resources including cluster tools and differential expression queries.

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DAVID (tool)

RRID:SCR_001881

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RRID:SCR_001757

Open source whole genome association analysis toolset, designed to perform range of basic, large scale analyses in computationally efficient manner. Used for analysis of genotype/phenotype data. Through integration with gPLINK and Haploview, there is some support for subsequent visualization, annotation and storage of results. PLINK 1.9 is improved and second generation of the software.

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LIMMA (tool)

RRID:SCR_010943

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