Fulp, C.T. et al. Identification of Arx transcriptional targets in the developing basal forebrain. Hum. Mol. Genet. 17, 3740-3760

Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Human Molecular Genetics (Impact Factor: 6.39). 10/2008; 17(23):3740-60. DOI: 10.1093/hmg/ddn271
Source: PubMed


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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    • "For example, knockout of the transcription factor aristaless-related homeobox (Arx) results in altered migration of interneurons and abnormal neuronal differentiation. Using Affymetrix arrays in a conditional knockout where Arx was depleted in the subpallium, Fulp et al. were able to reconstruct a genetic network where Arx normally represses additional transcription factors including Lmo1, Ebf3, and Shox2 (Fulp et al., 2008). As another example of the use of mutant mice, Prampano et al. compared gene expression in several different mutations that are associated with deficits in neuronal migrations (Lis1, Dcx, and Ywhae) and found alterations in classes of genes expressed (Pramparo et al., 2011). "
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    ABSTRACT: The transcriptome changes hugely during development of the brain. Whole genes, alternate exons, and single base pair changes related to RNA editing all show differences between embryonic and mature brain. Collectively, these changes control proteomic diversity as the brain develops. Additionally, there are many changes in noncoding RNAs (miRNA and lncRNA) that interact with mRNA to influence the overall transcriptional landscape. Here, we will discuss what is known about such changes in brain development, particularly focusing on high-throughput approaches and how those can be used to infer mechanisms by which gene expression is controlled in the brain as it matures.
    Full-text · Article · Aug 2014 · International Review of Neurobiology
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    • "The derivation of the ArxL/Y and Glucagon-Cre transgenic lines has previously been described [14], [15], [16]. To generate ArxL/Y;Glucagon-Cre mice, ArxL/+;Glucagon-Cre and ArxL/Y mice were mated on a BL6 background. "
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    ABSTRACT: The specification and differentiation of pancreatic endocrine cell populations (α-, β-, δ, PP- and ε-cells) is orchestrated by a combination of transcriptional regulators. In the pancreas, Aristaless-related homeobox gene (Arx) is expressed first in the endocrine progenitors and then restricted to glucagon-producing α-cells. While the functional requirement of Arx in early α-cell specification has been investigated, its role in maintaining α-cell identity has yet to be explored. To study this later role of Arx, we have generated mice in which the Arx gene has been ablated specifically in glucagon-producing α-cells. Lineage-tracing studies and immunostaining analysis for endocrine hormones demonstrate that ablation of Arx in neonatal α-cells results in an α-to-β-like conversion through an intermediate bihormonal state. Furthermore, these Arx-deficient converted cells express β-cell markers including Pdx1, MafA, and Glut2. Surprisingly, short-term ablation of Arx in adult mice does not result in a similar α-to-β-like conversion. Taken together, these findings reveal a potential temporal requirement for Arx in maintaining α-cell identity.
    Preview · Article · Jun 2013 · PLoS ONE
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    • "We then examined by transcriptomic experiments whether these genes were differently regulated following the ectopic expression of Arx in N2a cells or its knock-down in mouse ventral telencephalon (Quillé et al., 2011). For the latter, we used the publicly available microarray data generated by Fulp et al. (2008) and Colasante et al. (2009), comparing gene expression between basal telencephalon of E14.5 Arx knock-out and wild-type mice. Out of a total of 1006 genes which promoters were found to be enriched in Arx-immunoprecipitates, approximately 24% showed expression changes following Arx overexpression or knock-down (Quillé et al., 2011). "
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    ABSTRACT: Mutations in the homeobox transcription factor ARX have been found to be responsible for a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of intellectual disabilities without apparent brain abnormalities, but with associated features of dystonia and epilepsy. Arx expression is mainly restricted to populations of GABA-containing neurons. Studies of the effects of ARX loss of function, either in humans or mutant mice, revealed varying defects, suggesting multiple roles of this gene in brain patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. However, to date, little is known about how Arx functions as a transcription factor or which genes it binds and regulates. Recently, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified approximately 1000 gene promoters bound by Arx in transfected neuroblastoma N2a cells and mouse embryonic brain. To narrow the analysis of Arx targets to those most likely to control cortical interneuron migration and/or differentiation, we compare here our data to previously published studies searching for genes enriched or down-regulated in cortical interneurons between E13.5 and E15.5. We thus identified 14 Arx-target genes enriched (Cxcr7, Meis1, Ppap2a, Slc 12a5, Ets2, Phlda1, Egr1, Igf1, Lmo3, Sema6, Lgi1, Alk, Tgfb3, and Napb) and 5 genes specifically down-regulated (Hmgn3, Lmo1, Ebf3, Rasgef1b, and Slit2) in cortical migrating neurons. In this review, we present these genes and discuss how their possible regulation by Arx may lead to the dysfunction of GABAergic neurons, resulting in mental retardation and epilepsy.
    Full-text · Article · Dec 2011 · Frontiers in Cellular Neuroscience
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