Gene expression profile comparision between developing internerurons of wild type and poly Alanine expanded ARX mutants
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE273676 | GEO | 2026/02/28
REPOSITORIES: GEO
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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: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: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.
2026-02-28 | GSE274244 | GEO
Project description:Abnormal cortical interneuron (cIN) development and function has been linked to neurodevelopmental disorders including developmental epilepsies, intellectual disabilities, and autism spectrum disorder. Mutations in ARX (aristaless-related homeobox) are associated with these disorders. Its differential expression in projection neuron- versus interneuron progenitors suggests ARX is one of the few genes with distinct functions in each progenitor type. To investigate how ARX regulates development of cINs, which originate from the 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 expression and promotes cell cycle exit of the progenitor cells. Furthermore, it plays key roles 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.
2026-02-28 | GSE274243 | 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.
2008-08-30 | GSE12609 | GEO
Project description:Gene expression profile comparision between developing internerurons of wild type and poly Alanine expanded ARX mutants
| PRJNA1142601 | ENA
Project description:Roles of Arx in developing interneuron [scRNA-seq]
| PRJNA1145447 | ENA
Project description:Roles of Arx in developing interneuron [ChIP-seq]
| PRJNA1145448 | ENA
Project description:The homeobox containing gene Arx is expressed during ventral telencephalon development and it is required for correct GABAergic interneuron tangential migration from the ganglionic eminences to the olfactory bulbs, cerebral cortex and striatum. Its human ortholog is associated with a variety of neurological clinical manifestations whose syntoms are compatible with a loss of cortical interneurons and altered basal ganglia related-activities in humans. Herein, we reported the identification by global expression profiling of a group of genes whose expression is consistently altered in Arx mutant ganglionic eminences. Following analysis revealed the striking ectopic expression in the ganglionic eminences of a number of genes normally not, or only marginally, expressed in the ventral telencephalon. Among them, we functionally analyzed Ebf3, whose ectopic expression in ventral telencephalon is preventingneuronal tangential migration. Further, we showed that Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissue might marginally rescue tangential cell movements. Together, these data provide an initial analysis of the molecular pathways regulated by Arx and how their networking might regulate those specific cellular processes during telencephalon development strongly altered by loss of Arx. Three timed-pregnant Arx heterozygous dams crossed with C57Bl/6 males were sacrificed at E14.5, the embryos harvested and placed into cold PBS. After brain isolarion, meninges and olfactory bulbs were removed, and the ventral telencephalon separated from the overlying cerebral cortex. The same procedure was repeated for 5 wt and 5 Arx mutant embryos.
2010-03-09 | E-GEOD-12956 | biostudies-arrayexpress