Roles of Arx in developing interneuron [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE274243 | GEO | 2025/12/01
REPOSITORIES: GEO
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Project description:Abnormal cortical interneuron (cIN) development and function has been linked to neurodevelopmental disorders including developmental epilepsies, intellectual disabilities, and autism spectrum disorders. Mutations in ARX (aristaless-related homeobox), an X-linked transcription factor, are associated with these disorders. Its differential expression in pallial projection neuron- versus subpallial interneuron progenitors, suggests ARX is one of a few genes with distinct functions in each progenitor type. To investigate how ARX regulates development of cINs which originate from the subpallial ganglionic eminence (GE) and migrate to the cortex, we interrogated multiple GE-targeted Arx mutant mice. Our data demonstrates that ARX normally represses Nkx2.1 and promotes cIN differentiation. Furthermore, it plays a key role in cIN subtype specification and migration along the marginal zone by directly binding to the regulatory sequences of genes modulating cell subtype specification and cell-cell communication. Together these findings provide new insights into the mechanisms underlying cIN development and migration and how they are disrupted in several related disorders.
2025-12-01 | GSE274244 | GEO
Project description:Arx is a paired-box homeodomain transcription factor and the vertebrate ortholog to the Drosophila aristaless (al) gene. Mutations in Arx are associated with a variety of human diseases, including X-linked infantile spasm syndrome (OMIM: 308350), X-linked myoclonic epilepsy with mental retardation and spasticity (OMIM: 300432), X-linked lissencephaly with ambiguous genitalia (OMIM: 300215), X-linked mental retardation 54 (OMIM: 300419), and agenesis of the corpus callosum with abnormal genitalia (OMIM: 300004). Arx-deficient mice exhibit a complex, pleiotrophic phenotype, including decreased proliferation of neuroepithelial cells of the cortex, dysgenesis of the thalamus and olfactory bulbs, and abnormal nonradial migration of GABAergic interneurons. It has been suggested that deficits in interneuron specification, migration, or function lead to loss of inhibitory neurotransmission, which then fails to control excitatory activity and leads to epilepsy or spasticities. Given that Arx mutations are associated with developmental disorders in which epilepsy and spasticity predominate and that Arx-deficient mice exhibit deficits in interneuron migration, understanding the function of Arx in interneuron migration will prove crucial to understanding the pathology underlying interneuronopathies. Yet, downstream transcriptional targets of Arx, to date, remain unidentified. The aim of this project is to identify bona fide transcriptional targets for the Arx, a transcription factor required for normal migration of interneurons from the ganglionic eminences to the cortex, and to investigate the functions of these genes in the Arx-dependent pathway regulating nonradial neuronal migration. We hypothesize that the genes regulated by the Arx transcription factor will play a critical role in the nonradial migration of interneurons and that the results of this study will provide novel insights into the molecular mechanisms of nonradial neuronal migration, in particular, and possibly the molecular and biochemical pathogenesis underlying epilepsy, mental retardation, infantile spasm syndromes, and other so-called interneuronopathies;; We have recently generated a transgenic mouse with a floxed Arx allele (Arxflox). We have generated conditional knockouts in which Arx is removed specifically from the brain by mating Arxflox mice with transgenic mice expressing Cre behind the neural tube-specific transcriptional regulatory elements of the POU domain, class 3, transcription factor 4 promoter. Preliminary analyses of these mice suggest that conditional knockout mice recapitulate the nonradial migration defects associated with conventional knockout mice. We will compare the gene expression profiles of ganglion eminences (GEs; the anatomical source for nonradially migrating interneurons) from male Arxflox mice that express Pou3f-Cre to those from male mice without Arxflox allele. Animals will be prepared and sacrificed following our institutional protocol. Tissue will be rapidly dissected from E14.5 (the temporal peak of interneuron migration) GEs (MGE and LGE from both left and right hemispheres). Preliminary experiments suggest that the amounts of RNA that can be isolated from a pair of GEs is in the range of 2000-3500 ng, which should be sufficient for microarray analysis following linear amplification of RNA. The GEs from each animal will be combined, snap frozen in liquid nitrogen, and stored at -80 C until RNA is extracted. Total RNA will be extracted using Trizol followed by RNA purification with the RNeasy cleanup kit. We will be providing total RNA samples from four wildtype and four transgenic animals (true biological replicates) from three separate litters to mitigate any expression differences resulting from mouse to mouse or litter to litter variation.
2008-10-25 | E-GEOD-12609 | biostudies-arrayexpress
Project description:Arx is a paired-box homeodomain transcription factor and the vertebrate ortholog to the Drosophila aristaless (al) gene. Mutations in Arx are associated with a variety of human diseases, including X-linked infantile spasm syndrome (OMIM: 308350), X-linked myoclonic epilepsy with mental retardation and spasticity (OMIM: 300432), X-linked lissencephaly with ambiguous genitalia (OMIM: 300215), X-linked mental retardation 54 (OMIM: 300419), and agenesis of the corpus callosum with abnormal genitalia (OMIM: 300004). Arx-deficient mice exhibit a complex, pleiotrophic phenotype, including decreased proliferation of neuroepithelial cells of the cortex, dysgenesis of the thalamus and olfactory bulbs, and abnormal nonradial migration of GABAergic interneurons. It has been suggested that deficits in interneuron specification, migration, or function lead to loss of inhibitory neurotransmission, which then fails to control excitatory activity and leads to epilepsy or spasticities. Given that Arx mutations are associated with developmental disorders in which epilepsy and spasticity predominate and that Arx-deficient mice exhibit deficits in interneuron migration, understanding the function of Arx in interneuron migration will prove crucial to understanding the pathology underlying interneuronopathies. Yet, downstream transcriptional targets of Arx, to date, remain unidentified. The aim of this project is to identify bona fide transcriptional targets for the Arx, a transcription factor required for normal migration of interneurons from the ganglionic eminences to the cortex, and to investigate the functions of these genes in the Arx-dependent pathway regulating nonradial neuronal migration. We hypothesize that the genes regulated by the Arx transcription factor will play a critical role in the nonradial migration of interneurons and that the results of this study will provide novel insights into the molecular mechanisms of nonradial neuronal migration, in particular, and possibly the molecular and biochemical pathogenesis underlying epilepsy, mental retardation, infantile spasm syndromes, and other so-called interneuronopathies; We have recently generated a transgenic mouse with a floxed Arx allele (Arxflox). We have generated conditional knockouts in which Arx is removed specifically from the brain by mating Arxflox mice with transgenic mice expressing Cre behind the neural tube-specific transcriptional regulatory elements of the POU domain, class 3, transcription factor 4 promoter. Preliminary analyses of these mice suggest that conditional knockout mice recapitulate the nonradial migration defects associated with conventional knockout mice. We will compare the gene expression profiles of ganglion eminences (GEs; the anatomical source for nonradially migrating interneurons) from male Arxflox mice that express Pou3f-Cre to those from male mice without Arxflox allele. Animals will be prepared and sacrificed following our institutional protocol. Tissue will be rapidly dissected from E14.5 (the temporal peak of interneuron migration) GEs (MGE and LGE from both left and right hemispheres). Preliminary experiments suggest that the amounts of RNA that can be isolated from a pair of GEs is in the range of 2000-3500 ng, which should be sufficient for microarray analysis following linear amplification of RNA. The GEs from each animal will be combined, snap frozen in liquid nitrogen, and stored at -80 C until RNA is extracted. Total RNA will be extracted using Trizol followed by RNA purification with the RNeasy cleanup kit. We will be providing total RNA samples from four wildtype and four transgenic animals (true biological replicates) from three separate litters to mitigate any expression differences resulting from mouse to mouse or litter to litter variation.
2008-08-30 | GSE12609 | GEO
Project description:The Aristaless-related homeobox (ARX) gene is a transcription factor involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopemental disorders in humans, among which the most frequent, the 24 bp duplication in the protein polyalanine tract 2 (c.428_451dup24), gives rise to intellectual disability (ID), fine motor defects with or without epilepsy. To understand the physiological and functional consequences of this mutation, we generated and characterized a humanized mouse model carrying the c.428_451dup24 duplication (Arxdup24/0). Arxdup24/0 males presented with hyperactivity, enhanced stereotypies and altered contextual fear memory. Specific fine motor skills were also affected in Arxdup24/0 males, with reaching and grasping abilities alteration and fine motor coordination and balance defect. Transcriptome analysis of Arxdup24/0 forebrains at E15.5 showed a down-regulation of genes specifically expressed in interneurons associated with an up-regulation of interneuron silenced genes, suggesting abnormal interneuron development. Accordingly, interneuron migration and development were altered particularly in the cortex and the striatum between stages E15.5, P0 and adult. We also revealed a perturbation of the inhibitory/excitatory balance in Arxdup24/0 basolateral amygdala. Altogether, we showed that the c.428_451dup24 mutation modifies Arx function with a direct consequence on interneuron development, leading to hyperactivity and defects in precise motor movement control and in associative memory. Finally, we presented a new review of the clinical features of 33 male patients with ARX c.428_451dup24 mutation and showed striking similarities between their clinical features and the mouse phenotype.
2018-04-05 | GSE90036 | GEO
Project description:Infantile spasms (IS), a severe childhood epilepsy with an incidence of 1.6–4.5 per 10,000 live births, often lead to lifelong intellectual disability. Up to 5% of affected males carry mutations in the Aristaless-related homeobox (ARX) gene. The lack of human-specific models for developmental epilepsy limits progress, making organoids a promising alternative. We use human cortical (CO) and ganglionic eminence organoids (GEO) to model poly-alanine expansion (PAE) mutations in ARX. PAE mutations increase cortical progenitor proliferation and accelerate early cortical development. ARX expression is upregulated in patient-derived COs at 30 DIV, correlating with altered cell cycle gene expression. We observe enhanced, cell-autonomous interneuron migration, which is rescued by CXCR4 inhibition. ARXPAE assembloids exhibit early network hyperactivity. These findings highlight the utility of human brain organoids in uncovering ARXPAE-driven mechanisms and represent a critical step toward developing targeted therapies for IS and related developmental epilepsies.
2025-11-20 | GSE215362 | GEO
Project description:Aristaless-related homeobox (ARX) is an X-linked gene encoding a bi-functional morphogenetic transcription factor with a key role in neuronal migration and brain development. Mutations in ARX have been identified in patients with X-linked Lissencephaly with Abnormal Genitalia (XLAG) and Early-infantile epileptic encephalopathy (EIEE). The aim of this project was to perform a proteomic analysis in whole neonatal brains isolated from XLAG and EIEE mouse models, ArxKO/Y and Arx(GCG)7/Y, to compare the mutant proteome profiles versus the wild-type ones by LC-MS/MS. By comparing the two proteomics profiles, common and different protein regulations emerged. Collectively, these findings could provide novel molecular insights into the proteomic mechanisms underlying XLAG and EIEE pathogenesis and may accelerate the design of pathway-guided therapeutic interventions for ARX-endophenotypes.
2024-06-14 | PXD021358 | Pride
Project description:Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Some of these promoters were enriched for a sequence very similar to a motif previously identified as Arx-binding motif and approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development, including axonal guidance and synaptic plasticity and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations. N2a cells were transfected with either Arx or the corresponding empty vector. Eight different independent experiments were performed. The 16 samples were randomly distributes on the 2 expression microarrays.
2011-12-22 | E-GEOD-30190 | biostudies-arrayexpress
Project description:Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Some of these promoters were enriched for a sequence very similar to a motif previously identified as Arx-binding motif and approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development, including axonal guidance and synaptic plasticity and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations. ChIP-Chip experiments were performed with either Arx transfected N2a cells or mouse embryonic brains (E15.5). Three replicates were performed for each condition.
2011-12-22 | E-GEOD-29985 | biostudies-arrayexpress
Project description:Cortical interneuron (CIN) dysfunction is thought to play a major role in neuropsychiatric conditions like epilepsy, schizophrenia and autism. It is therefore essential to understand how the development, physiology and functions of CINs influence cortical circuit activity and behavior in model organisms such as mice and primates. We sought to discover gene regulatory enhancer elements (REs) that can be used in AAV viral vectors to drive expression in CINs through systematic genome-wide identification of putative REs (pREs) that are preferentially active in immature CINs by histone modification ChIP-seq. We evaluated two novel pREs in AAV vectors, alongside the well-established Dlx I12b enhancer, and found that they drove CIN-specific reporter expression in adult mice.
2020-09-24 | GSE158428 | GEO
Project description:Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Some of these promoters were enriched for a sequence very similar to a motif previously identified as Arx-binding motif and approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development, including axonal guidance and synaptic plasticity and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations.
2011-12-22 | GSE30190 | GEO