Modeling the functional genomics of autism using human neurons

• Published in: Molecular psychiatry Vol. 17; no. 2; pp. 202 - 214
• Main Authors: KONOPKA, G, WEXLER, E, GESCHWIND, D. H, ROSEN, E, MUKAMEL, Z, OSBORN, G. E, CHEN, L, LU, D, GAO, F, GAO, K, LOWE, J. K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.02.2012
• Subjects: Animal models; Autism; Autistic Disorder - genetics; Autistic Disorder - pathology; Biological and medical sciences; Cell Differentiation - physiology; Cells, Cultured; Child clinical studies; Developmental disorders; Fetus; Fetuses; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental - genetics; Gene regulation; Genetic aspects; Genetic engineering; Genomics; Genotype; Gestational Age; Growth factors; Humans; Infantile autism; Ki-67 Antigen - metabolism; Medical sciences; Mental disorders; Models, Genetic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural stem cells; Neural Stem Cells - physiology; Neurodevelopmental disorders; Neurons; Neurons - metabolism; Oligonucleotide Array Sequence Analysis; Physiological aspects; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Transcription; United States; Human; Neuropsychiatry; Genomics; Developmental disorder; Genetic determinism; Autism; neuropsychiatric disease; Neuron; pharmacogenomics; neurodevelopment; high-throughput drug screen; Mental disorder; Genetics; model system; Models
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2011.60

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.