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Modeling the functional genomics of autism using human neurons.

Molecular psychiatry | Feb 24, 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

Mesh terms: Autistic Disorder | Cell Differentiation | Cells, Cultured | Fetus | Gene Expression Profiling | Gene Expression Regulation, Developmental | Genomics | Genotype | Gestational Age | Humans | Ki-67 Antigen | Models, Genetic | Nerve Tissue Proteins | Neural Stem Cells | Neurons | Oligonucleotide Array Sequence Analysis

Research resources used in this publication

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Associated grants

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

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Database for Annotation Visualization and Integrated Discovery

A database which provides a comprehensive set of functional annotation tools for investigators to understand biological meaning behind large list of genes. For any given gene list, DAVID tools are able to perform a variety of actions such as identifying enriched biological themes (particularly GO terms), discovering enriched functional-related gene groups, clustering redundant annotation terms, and visualizing genes on BioCarta and KEGG pathway maps.

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Allen Institute for Brain Science

Independent 501(c)(3) nonprofit medical research organization dedicated to accelerating the understanding of how the human brain works. Utilizing the mouse model system, a multidisciplinary group of neuroscientists, molecular biologists, informaticists, engineers, mathematicians, statisticians, and computational biologists have joined together to investigate expression of 20,000 genes in the adult mouse brain and to map gene expression to a cellular level beyond neuroanatomic boundaries. The data generated from this joint effort is contained in the publicly available Allen Brain Atlas application. Molecular approaches to understanding the functional organization of the brain promise new insights into the relationships between genes, brain, behavior and disease. To facilitate such insights, the Allen Institute produces large-scale projects and makes the resulting data and tools freely available online to scientists worldwide. These open resources, all available at www.brain-map.org, are intended to foster scientific discovery and collaboration. Atlases: Allen Developing Mouse Brain Atlas: A map of gene expression in the developing mouse brain. Building on the Allen Mouse Brain Atlas, this atlas reveals gene expression patterns from embryonic through postnatal stages to provide information about both spatial and temporal regulation of gene expression. Allen Spinal Cord Atlas: A genome-wide map of gene expression throughout the adult and juvenile mouse spinal cord. The Atlas was made possible through the generous support of a diverse consortium of funders, representing disease organizations, foundations, and corporate and private donors. Allen Mouse Brain Atlas (formerly Allen Brain Atlas): A genome-wide, three-dimensional map of gene expression in the adult mouse brain. Similar in scale to the Human Genome Project, the Atlas reveals the expression patterns of approximately 20,000 genes throughout the entire adult mouse brain down to the cellular level. The Allen Institutes inaugural project, the Atlas was completed in 2006. Studies: Mouse Diversity Study: Characterization of gene expression in the brain across genetic backgrounds and sex. Expanding on the Allen Mouse Brain Atlas, this resource includes data for 49 pharmaceutical drug target genes and a selected set of additional genes across seven mouse strains and in female mice. Transgenic Mouse Study: Comprehensive characterization of the expression patterns of genetically-controlled markers or tool genes in the brains of transgenic mice. Providing standardized, detailed, anatomical profiling of transgene expression throughout the brain, this dataset is intended to reveal the potential of each transgenic mouse line and help researchers choose the appropriate tools for their studies. Human Cortex Study: A collection of gene expression data in the adult human neocortex. Providing data for several categories of genes across different cortical regions and human individuals, including control and schizophrenic cases, the dataset has the potential to enable exploration of variability in cortical gene expression across different ages, between genders across different regions of the cortex and in schizophrenia. Sleep Study: A comprehensive collection of gene expression data in the mouse brain for five different conditions of sleep and wakefulness. Generated in collaboration with SRI International, this unique dataset is intended to help sleep researchers advance understanding of sleep deprivation and the dynamic changes underlying sleep/wake cycles. The sleep study was funded by an award from the U.S. Department of Defense.

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Gene Expression Omnibus

A public functional genomics data repository supporting MIAME-compliant data submissions. Tools are provided to help users query and download experiments and curated gene expression profiles. These data include 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.

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