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.
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Acknowledgements
This work is supported by grants from the NIMH (R37MH060233 and R01MH081754) to DHG and the Shappel-Guerin Foundation. GK is supported by an A.P. Giannini Foundation Medical Research Fellowship, a NARSAD Young Investigator Award, and the NIMH (K99MH090238). EW is supported by the NIMH (K08MH074362). Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland (NICHD Contract numbers N01-HD-4-3368 and N01-HD-4-3383). The role of the NICHD Brain and Tissue Bank is to distribute tissue and therefore cannot endorse the studies performed or the interpretation of results.
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Konopka, G., Wexler, E., Rosen, E. et al. Modeling the functional genomics of autism using human neurons. Mol Psychiatry 17, 202–214 (2012). https://doi.org/10.1038/mp.2011.60
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DOI: https://doi.org/10.1038/mp.2011.60
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