Gene expression profile comparision between developing internerurons of wild type and poly Alanine expanded ARX mutants
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PROVIDER: PRJNA1142601 | ENA |
REPOSITORIES: ENA
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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:Dual developmental effects of ARX poly-alanine mutations in human cortical excitatory and inhibitory neurons
| PRJNA889848 | ENA
Project description:RqcH and RqcP catalyze processive poly-alanine synthesis
| PRJNA728973 | ENA
Project description:We applied RNA-seq analysis to human islet cells, received from 3 independent donors, treated with either redifferentiation cocktail + ARX shRNA, or redifferentiation cocktail + control shRNA or left untreated.
2016-06-20 | GSE73433 | GEO
Project description:In the cell, stalled ribosomes are rescued through ribosome-associated protein quality-control (RQC) pathways. We demonstrate that RqcH is responsible for tRNAAla selection during RQC elongation, whereas RqcP lacks any tRNA specificity. The ribosomal protein uL11 is crucial for RqcH, but not RqcP, recruitment to the 50S subunit, and B. subtilis lacking uL11 are RQC-deficient. Through mutational mapping, we identify critical residues within RqcH and RqcP that are important for interaction with the P-site tRNA and/or the 50S subunit. Collectively, our findings provide mechanistic insight into the role of RqcH and RqcP in the bacterial RQC pathway. the synthesis of C-terminal poly-Alanine ‘tail’. While it is well-established that RqcP and RqcH are essential for poly-Alanine-tailing in living cells, here, by reconstituting the RQC elongation biochemically we provide a direct proof that the two factors are sufficient. We demonstrate that while RqcH is responsible for tRNAAla selection during RQC elongation, RqcP lacks the tRNA specificity. Through mutational mapping we show that stable interaction of RqcP with 23S rRNA – but not with tRNA – is crucial for RQC, supporting the role of the E-site bound RqcP as a pawl of RQC elongation ratchet. We show that ribosomal protein uL11 is crucial for RqcH – but nor RqcP – recruitment to 50S, and B. subtilis lacking uL11 is RQC-deficient. Finally, we show that proteins encoded by non-stop mRNAs are not universally efficiently targeted by RQC, and that simultaneous disruption of RQC and trans-translation results in bacterial filamentation
2021-08-19 | GSE174254 | 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: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:Comparision of mRNA abundance and translation efficiency mediated by cytoplasmic poly(A) polymerases in C. elegans
2014-10-02 | GSE58918 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE29985: Identification by ChIP-on-Chip of ARX target genes, a transcription factor implicated in mental retardation and epilepsy GSE30190: Comparison of gene expression between Arx-transfected N2a cells and cells transfected by the corresponding empty vector Refer to individual Series
2011-12-22 | E-GEOD-30191 | 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. 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