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Identification of Arx transcriptional targets in the developing basal forebrain.

Human molecular genetics | Dec 1, 2008

Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations.

Pubmed ID: 18799476 RIS Download

Mesh terms: Animals | Gene Expression Regulation, Developmental | Gene Regulatory Networks | Homeodomain Proteins | Humans | Intellectual Disability | Mice | Mice, Inbred C57BL | Mice, Transgenic | Molecular Sequence Data | Prosencephalon | Transcription Factors | Transcription, Genetic

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS046616
  • Agency: NINDS NIH HHS, Id: NS46616
  • Agency: NICHD NIH HHS, Id: P30HD26979

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GenePaint.org

A digital atlas of gene expression patterns in the developing and adult mouse. Several reference atlases are also available through this site. Expression patterns are determined by non-radioactive in situ hybridization on serial tissue sections. Sections were labeled using non radioactive in situ hybridization with riboprobes and annotated for level of gene expression (not detected, weak, medium, strong) and pattern (ubiquitous, regional, scattered). Sections are available from several developmental ages: E10.5, E14.5 (whole embryos), E15.5, P7 and P56 (brains only). To retrieve expression patterns, search by gene name, site of expression, GenBank accession number or sequence homology. For viewing expression patterns, GenePaint.org features a virtual microscope tool that enables zooming into images down to cellular resolution.

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NIH Neuroscience Microarray Consortium

THIS RESOURCE IS NO LONGER IN SERVICE, documented on April 24, 2012. (no longer being funded) The NIH Microarray Consortium provides for-fee services to a community of NIH grantees, together with a more limited set of services to the public. The primary goal of this consortium is to move basic and translational research forward through acquisition and dissemination of high quality genomic data. This site includes a repository of microarray data sets and offers one-click links to public projects. These datasets were generated by various researchers on these platforms: Affymetrix, Agilent, Ambion, cDNA, Illumina, and Operon. The species currently covered are: Arabidopsis, Bovine, chicken, C. Elegans, Drosophila, Human, Macaca mulatta (Rhesus macaque), Mouse, Rat, Songbird, Xenopus, Yeast, and zebra finch. Basic search functions allows users to choose multiple options for finding the projects that interest them, and raw data files can also be downloaded after user registration. Web-based data analysis tools are also available. Scientists can analyze microarray data from the consortium repository or investigators can upload outside data for analysis.

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Bioconductor

A catalog of tools and software packages for the analysis and comprehension of high-throughput genomic data that uses the R statistical programming language. Bioconductor has a development version to which new features and packages are added prior to incorporation in the release. A large number of meta-data packages provide pathway, organism, microarray and other annotations. The broad goals of the Bioconductor project are: to provide widespread access to a broad range of powerful statistical and graphical methods for the analysis of genomic data; to facilitate the inclusion of biological metadata in the analysis of genomic data; to provide a common software platform that enables the rapid development and deployment of extensible, scalable, and interoperable software; and to train researchers on computational and statistical methods for the analysis of genomic data.

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