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Identification of Arx transcriptional targets in the developing basal forebrain
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 d...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581427/ https://www.ncbi.nlm.nih.gov/pubmed/18799476 http://dx.doi.org/10.1093/hmg/ddn271 |
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author | Fulp, Carl T. Cho, Ginam Marsh, Eric D. Nasrallah, Ilya M. Labosky, Patricia A. Golden, Jeffrey A. |
author_facet | Fulp, Carl T. Cho, Ginam Marsh, Eric D. Nasrallah, Ilya M. Labosky, Patricia A. Golden, Jeffrey A. |
author_sort | Fulp, Carl T. |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2581427 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-25814272009-02-25 Identification of Arx transcriptional targets in the developing basal forebrain Fulp, Carl T. Cho, Ginam Marsh, Eric D. Nasrallah, Ilya M. Labosky, Patricia A. Golden, Jeffrey A. Hum Mol Genet Articles 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. Oxford University Press 2008-12-01 2008-09-16 /pmc/articles/PMC2581427/ /pubmed/18799476 http://dx.doi.org/10.1093/hmg/ddn271 Text en © 2008 The Author(s) |
spellingShingle | Articles Fulp, Carl T. Cho, Ginam Marsh, Eric D. Nasrallah, Ilya M. Labosky, Patricia A. Golden, Jeffrey A. Identification of Arx transcriptional targets in the developing basal forebrain |
title | Identification of Arx transcriptional targets in the developing basal forebrain |
title_full | Identification of Arx transcriptional targets in the developing basal forebrain |
title_fullStr | Identification of Arx transcriptional targets in the developing basal forebrain |
title_full_unstemmed | Identification of Arx transcriptional targets in the developing basal forebrain |
title_short | Identification of Arx transcriptional targets in the developing basal forebrain |
title_sort | identification of arx transcriptional targets in the developing basal forebrain |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581427/ https://www.ncbi.nlm.nih.gov/pubmed/18799476 http://dx.doi.org/10.1093/hmg/ddn271 |
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