Human Molecular Genetics Advance Access originally published online on September 16, 2008
Human Molecular Genetics 2008 17(23):3740-3760; doi:10.1093/hmg/ddn271
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Identification of Arx transcriptional targets in the developing basal forebrain
1 Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA 2 Department of Pathology 3 Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA 4 Vanderbilt Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
* To whom correspondence should be addressed at: Department of Pathology, Abramson Research Center, Room 516C, Children’s Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA. Tel: +1 2155904307; Fax: +1 2155903709; Email: goldenj{at}mail.med.upenn.edu
Received June 4, 2008; Revised August 1, 2008; Accepted August 27, 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.
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