Modeling the functional genomics of autism using human neurons

G. Konopka, E. Wexler, E. Rosen, Z. Mukamel, G. E. Osborn, L. Chen, D. Lu, F. Gao, K. Gao, J. K. Lowe, D. H. Geschwind

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)202-214
Number of pages13
JournalMolecular psychiatry
Volume17
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • high-throughput drug screen
  • model system
  • neurodevelopment
  • neuropsychiatric disease
  • pharmacogenomics

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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  • Cite this

    Konopka, G., Wexler, E., Rosen, E., Mukamel, Z., Osborn, G. E., Chen, L., Lu, D., Gao, F., Gao, K., Lowe, J. K., & Geschwind, D. H. (2012). Modeling the functional genomics of autism using human neurons. Molecular psychiatry, 17(2), 202-214. https://doi.org/10.1038/mp.2011.60