Affinage

ARX

Homeobox protein ARX · UniProt Q96QS3

Length
562 aa
Mass
58.2 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARX encodes a paired-type homeodomain transcription factor that operates primarily as a transcriptional repressor to govern GABAergic interneuron development, cortical progenitor proliferation, and pancreatic endocrine cell fate specification. In the developing forebrain, ARX functions downstream of Dlx2 and Lhx6 and directly represses targets including Ebf3, Lmo1, Shox2, and Cdkn1c to control interneuron tangential migration from the ganglionic eminence and intermediate progenitor cell cycling in the cortex; interneuron-specific Arx loss is sufficient to cause developmental epilepsy resembling infantile spasms (PMID:12379852, PMID:18923043, PMID:19627984, PMID:23968833). In the pancreas, ARX and Pax4 mutually repress each other to antagonistically specify alpha- versus beta/delta-cell fates, with ARX sufficient to convert beta cells into glucagon-producing cells and its silencing in beta cells maintained by a Dnmt1–MeCP2–PRMT6 epigenetic cascade; alpha-cell-specific Arx deletion induces conversion to functional beta-like cells (PMID:14561778, PMID:17404619, PMID:21497756, PMID:24204325). Homeodomain missense mutations abolish DNA binding and transcriptional repression with severity correlating to clinical phenotype, while polyalanine tract expansions reduce protein abundance and can cause nuclear inclusion formation (PMID:22194193, PMID:15533998, PMID:24122442).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    The foundational question of what ARX does in vivo was answered: Arx knockout revealed essential roles in forebrain neuroblast proliferation, GABAergic interneuron migration/differentiation, and testicular development, establishing ARX as a key neurodevelopmental transcription factor.

    Evidence Arx knockout mouse with morphological and histological analysis

    PMID:12379852

    Open questions at the time
    • Downstream transcriptional targets unknown
    • Mechanism of action (activator vs. repressor) not yet determined
    • Pancreatic role not yet explored
  2. 2003 High

    ARX was established as a master switch for pancreatic endocrine cell fate: Arx loss eliminates alpha cells while expanding beta/delta populations, and Arx and Pax4 were shown to act as mutual antagonists specifying endocrine lineage identity.

    Evidence Arx and Pax4 single and double knockout mice with immunohistology and RT-PCR

    PMID:14561778 PMID:15930104

    Open questions at the time
    • Whether Arx directly represses Pax4 transcription not yet tested by ChIP
    • Sufficiency of Arx for alpha-cell conversion not yet demonstrated
  3. 2004 High

    The pathological mechanism of polyalanine expansion mutations was addressed: expanded polyalanine tracts cause nuclear aggregation into ubiquitinated inclusions that recruit Hsp70 and increase cell death, providing a protein-misfolding model for ARX-associated disease.

    Evidence Cell culture and brain slice transfection with fluorescence microscopy and Hsp70 rescue

    PMID:15533998

    Open questions at the time
    • Whether inclusions form in vivo in patient or knock-in brains not yet shown
    • Later knock-in models found reduced abundance without aggregates, suggesting context dependence
  4. 2007 High

    ARX sufficiency for cell fate conversion was demonstrated: forced Arx expression in beta cells converted them to glucagon/PP-producing cells in vivo, proving ARX alone can instruct alpha/PP identity and suppress beta/delta fate.

    Evidence Conditional gain-of-function mouse with lineage tracing and quantitative RT-PCR

    PMID:17404619

    Open questions at the time
    • Electrophysiological functionality of converted cells not tested
    • Direct versus indirect transcriptional targets mediating conversion not identified
  5. 2007 Medium

    An unexpected muscle role was uncovered: ARX physically interacts with Mef2C and synergizes with MyoD to activate myogenic transcription, with Arx-deficient myoblasts showing delayed differentiation.

    Evidence Co-immunoprecipitation with Mef2C, reporter assays, Arx KO myoblast analysis

    PMID:17932502

    Open questions at the time
    • Single lab, no reciprocal IP or in vivo muscle-specific deletion
    • Relevance to human muscle disease unknown
    • Activator function here contrasts with repressor role in brain—mechanism of context switching unclear
  6. 2008 High

    The regulatory hierarchy controlling ARX in interneurons was established and direct transcriptional targets identified: Dlx2 directly activates Arx through ultraconserved enhancers, and ARX directly represses Ebf3, Lmo1, and Shox2 in the subpallium, with genome-wide profiling revealing ~84 dysregulated migration/axon guidance genes.

    Evidence Enhancer assays, Dlx gain/loss-of-function in Arx mutants, ChIP validation of direct targets, genome-wide expression in Arx-null subpallium

    PMID:18509041 PMID:18799476 PMID:18923043

    Open questions at the time
    • Full enhancer logic (combinatorial inputs) not resolved
    • Which of the 84 dysregulated genes are direct versus indirect targets not fully determined
  7. 2009 High

    The cellular substrate of ARX-associated epilepsy was defined: interneuron-specific Arx deletion causes infantile spasms with EEG correlates, and the polyalanine expansion knock-in reveals selective loss of calbindin+ cortical and NPY/cholinergic striatal interneurons, while direct repression of Ebf3 controls tangential migration.

    Evidence Dlx5/6-Cre conditional KO with EEG, polyalanine knock-in model with interneuron subtype quantification, Ebf3 epistasis rescue

    PMID:19439424 PMID:19587282 PMID:19627984

    Open questions at the time
    • Why calbindin+ but not parvalbumin+ interneurons are selectively vulnerable remains unexplained
    • Whether seizure phenotype is purely from interneuron loss or also involves circuit-level remodeling not resolved
  8. 2011 High

    The epigenetic mechanism silencing ARX in beta cells was deciphered: Dnmt1-mediated methylation of the Arx locus recruits MeCP2 and PRMT6 to enforce H3R2 methylation and transcriptional repression; loss of this cascade converts beta cells to alpha cells. Separately, Isl-1 was shown to activate Arx transcription in alpha cells through conserved regulatory elements, and ARX was found to regulate the chromatin remodeler KDM5C.

    Evidence Dnmt1 conditional KO with bisulfite sequencing and ChIP; Isl-1 ChIP and reporter assays; ARX ChIP at KDM5C locus with H3K4me3 readout; genome-wide ChIP-chip

    PMID:21388963 PMID:21497756 PMID:21966449 PMID:23246292

    Open questions at the time
    • Whether PRMT6-mediated H3R2me is the sole chromatin effector or acts redundantly with other marks
    • Full scope of the ~1006 ARX-bound promoters not functionally validated
  9. 2012 High

    The molecular basis of homeodomain mutations was resolved: missense mutations abolish DNA binding (by EMSA and ChIP) and transcriptional repression, with severity correlating to clinical phenotype; flanking sequences influence DNA binding specificity. A separate polyalanine knock-in revealed epilepsy can arise from excitatory network remodeling rather than interneuron loss alone.

    Evidence EMSA and ChIP with mutation panels, luciferase repression assays; knock-in mouse electrophysiology

    PMID:22194193 PMID:22252899 PMID:22628459

    Open questions at the time
    • No crystal structure of ARX homeodomain–DNA complex available
    • How partial DNA-binding mutations (e.g. P353L) produce milder phenotypes mechanistically is not resolved at the structural level
  10. 2013 High

    Two key advances were made: ARX was shown to directly repress Cdkn1c to maintain cortical progenitor proliferation, explaining microcephaly in ARX mutations; and alpha-cell-specific Arx deletion was demonstrated to convert alpha to functional beta-like cells at any age, independent of Pax4, establishing ARX as a therapeutic target for diabetes.

    Evidence Cortex-specific CKO with ChIP at Cdkn1c; alpha-cell-specific Arx deletion with lineage tracing and glucose tolerance; polyalanine knock-in protein quantification

    PMID:23968833 PMID:24122442 PMID:24204325

    Open questions at the time
    • Scalability and long-term stability of alpha-to-beta conversion not established for clinical translation
    • Whether Cdkn1c derepression fully accounts for the proliferative phenotype or other cell-cycle targets contribute
  11. 2014 High

    The upstream regulatory hierarchy was extended: Lhx6 directly binds an Arx enhancer to control interneuron specification (with Arx as an effector restoring Lhx6-null fate defects), and ARX was shown to act as a context-dependent activator at the Shh floor plate enhancer in a FoxA2-dependent feedback loop.

    Evidence In vivo ChIP at Arx enhancer with MGE transplant rescue; chick electroporation and Arx KO mouse for Shh enhancer binding

    PMID:24742460 PMID:24968361

    Open questions at the time
    • How ARX switches between repressor and activator function in different tissues remains mechanistically undefined
    • Cofactors mediating context-dependent activation not identified
  12. 2017 High

    Translational potential was strengthened: combined Dnmt1/Arx loss in alpha cells drives extensive conversion to electrophysiologically functional beta-like cells, validated by single-cell RNA-seq and observed in human T1D pancreas tissue.

    Evidence Conditional double KO with lineage tracing, scRNA-seq, electrophysiology, GSIS assay, human tissue analysis

    PMID:28215845

    Open questions at the time
    • Whether pharmacological ARX inhibition can replicate genetic deletion in human islets
    • Immune evasion of converted cells in T1D context not addressed
  13. 2020 High

    Postnatal roles of ARX were revealed: Arx continues to regulate parvalbumin interneuron function after development, with postnatal PV-specific deletion causing intrinsic hypoexcitability, altered theta oscillations, seizures, and anxiety through changes in synaptic and extracellular matrix gene expression.

    Evidence PV-specific conditional KO, EEG, whole-cell patch-clamp, FACS-sorted PVI transcriptomics, behavioral testing

    PMID:33490907

    Open questions at the time
    • Whether ARX maintains PV interneuron identity throughout adulthood or only during a postnatal critical period
    • Direct versus indirect transcriptional targets in mature PV cells not distinguished by ChIP

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how ARX switches between repressor and activator modes in different tissues, what cofactors or post-translational modifications dictate this switch, whether pharmacological modulation of ARX activity is feasible for diabetes or epilepsy therapy, and whether a structural model of the ARX homeodomain–DNA complex can explain genotype-phenotype correlations.
  • No crystal or cryo-EM structure of ARX or its homeodomain–DNA complex
  • Cofactors mediating repressor-to-activator switch unidentified
  • No pharmacological modulators of ARX reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 7 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-112316 Neuronal System 3 R-HSA-4839726 Chromatin organization 2
Partners
DLX2FOXA2IPO13ISL1LHX6MECP2MEF2CPAX4

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ARX/Arx loss-of-function causes suppressed proliferation of forebrain neuroblasts and aberrant migration/differentiation of GABAergic interneurons in the ganglionic eminence and neocortex, as well as abnormal testicular differentiation, established in knockout mice. Knockout mouse with morphological and histological analysis Nature genetics High 12379852
2003 Arx is required for pancreatic alpha-cell fate acquisition and simultaneously represses beta- and delta-cell destiny; Arx and Pax4 act antagonistically and mutually repress each other's transcripts to specify endocrine cell lineages. Arx knockout mouse, immunohistology, RT-PCR for hormone and transcription factor expression Genes & development High 14561778
2007 Forced misexpression of Arx in embryonic or adult beta cells converts them into glucagon- or PP-producing (alpha/PP) cells, demonstrating Arx is sufficient to instruct alpha/PP cell fate and suppress beta/delta cell identity in vivo. Conditional gain-of-function mouse, lineage tracing, quantitative RT-PCR, immunohistology The Journal of clinical investigation High 17404619
2005 In the combined absence of Arx and Pax4, pancreatic alpha- and beta-cells are lost and virtually all endocrine progenitors adopt a somatostatin-producing delta-cell fate; Arx and Pax4 act as transcriptional repressors that control expression of one another. Double-knockout mouse, immunohistology, epistasis analysis Development (Cambridge, England) High 15930104
2008 Arx is a direct transcriptional target of Dlx2 in GABAergic neurons; Dlx overexpression induces ectopic Arx expression through ultraconserved enhancer elements downstream of the Arx coding region, and Arx mediates Dlx-dependent promotion of interneuron tangential migration but is not required for GABAergic cell fate commitment. Enhancer characterization, Dlx gain- and loss-of-function in Arx or Dlx mutant tissues, in vivo reporter assays The Journal of neuroscience High 18923043
2008 Arx cell-autonomously regulates cortical progenitor cell cycle (both exit and length) and neuronal migration; ARX knockdown prevents multipolar morphology in SVZ/IZ and impairs radial migration of pyramidal neurons, while overexpression promotes tangentially oriented processes; both loss and overexpression of ARX impair tangential migration of GABAergic interneurons. In utero electroporation with RNAi knockdown and overexpression constructs, live imaging, morphological analysis The Journal of neuroscience High 18509041
2007 Arx inactivation in the ventral telencephalon causes periventricular accumulation of immature neurons in LGE and MGE, impairs both tangential and radial migration, results in loss of cholinergic neurons, and disrupts thalamocortical projections; mutant neurons retain differentiation potential in vitro but show cell-autonomous deficits in migration. Arx knockout mouse analysis, in vitro neuronal migration assay, immunohistology The Journal of neuroscience High 17460091
2008 Arx directly represses three transcription factors in the developing basal forebrain: Lmo1, Ebf3, and Shox2; genome-wide expression profiling identified 84 dysregulated genes in Arx-null subpallium enriched for cell migration, axon guidance, and neurogenesis functions. Genome-wide expression screen in Arx-null subpallium, chromatin immunoprecipitation-validated direct repression of target genes Human molecular genetics High 18799476
2009 Conditional deletion of Arx from ganglionic eminence-derived interneurons causes early-life seizures resembling infantile spasms with electrographic features, demonstrating that interneuron-specific Arx loss is sufficient to produce developmental epilepsy. Conditional knockout (Dlx5/6-Cre), EEG recording, behavioral analysis Brain High 19439424
2009 The Arx(GCG)10+7 polyalanine expansion knock-in mouse displays interneuronopathy with selective reduction of calbindin-positive (but not parvalbumin- or calretinin-positive) cortical interneurons and NPY/cholinergic striatal interneurons, spontaneous spasms, multifocal EEG spikes, and cognitive/behavioral deficits, establishing interneuron-specific pathology as the substrate for the ISS phenotype. Knock-in mouse model, EEG, immunohistochemistry, neurobehavioral testing The Journal of neuroscience High 19587282
2004 Polyalanine tract expansions in Arx cause nuclear protein aggregation forming filamentous ubiquitinated inclusions that recruit Hsp70, and result in increased cell death; co-expression of Hsp70 reduces inclusion formation. Cell culture transfection, brain slice transfection, fluorescence microscopy, ubiquitin immunostaining The Journal of cell biology High 15533998
2011 In pancreatic beta cells, the Arx locus is methylated and repressed; Dnmt1-deficient beta cells show Arx hypomethylation and expression, converting to alpha cells. The methylated Arx locus is bound by MeCP2, which recruits PRMT6 to methylate histone H3R2, enforcing transcriptional repression of Arx. Dnmt1 conditional knockout, bisulfite sequencing, ChIP for MeCP2 and PRMT6, histone methylation assay, lineage tracing Developmental cell High 21497756
2013 Selective inhibition of Arx in adult pancreatic alpha cells is sufficient to convert them into functional beta-like cells at any age; this conversion also mobilizes duct-lining precursor cells to adopt glucagon+ fates that are subsequently converted to beta-like cells. Pax4 is dispensable for this regeneration, identifying Arx as the primary trigger of alpha-to-beta-like cell neogenesis. Conditional loss-of-function (alpha-cell-specific Arx deletion), lineage tracing, Arx/Pax4 double conditional mutants, functional glucose tolerance assays PLoS genetics High 24204325
2017 Combined loss of Dnmt1 and Arx in mouse alpha cells causes extensive conversion into beta-like cells with native beta-cell electrophysiology and glucose-stimulated insulin secretion, confirmed by single-cell RNA-seq and lineage tracing; in human T1D patients, subsets of glucagon-expressing cells with loss of DNMT1 and ARX produce insulin and beta-cell factors. Conditional double knockout, lineage tracing, single-cell RNA-seq, electrophysiology, GSIS assay, human tissue analysis Cell metabolism High 28215845
2009 Arx acts as a regional selector gene in the ventral telencephalon primarily through transcriptional repression; it directly represses Ebf3 in the ganglionic eminence, and ectopic Ebf3 expression prevents tangential migration, while Ebf3 silencing in Arx mutants partially rescues tangential cell movement. Gene expression profiling in Arx mutant GE, in vivo rescue experiments, functional epistasis Developmental biology High 19627984
2013 ARX directly represses Cdkn1c (a cell cycle inhibitor) in cortical progenitors; loss of pallial Arx results in Cdkn1c overexpression, reduced intermediate progenitor cell (IPC) proliferation, and consequent reduction of upper-layer neurons. Cortex-specific conditional KO, transcriptional profiling, ChIP for direct ARX binding to Cdkn1c locus, immunohistology Cerebral cortex High 23968833
2010 Missense mutations in the nuclear localization sequences (NLS) flanking the ARX homeodomain disrupt nuclear accumulation not by abolishing binding to importin IPO13, but by preventing release of ARX from IPO13 in the RanGTP-rich nuclear environment, causing cytoplasmic sequestration; cells expressing these mutant ARX proteins accumulate in mitosis. TUBA1A (alpha-tubulin) was identified as a novel ARX-interacting protein. Co-immunoprecipitation, immunofluorescence, cell division analysis, novel interactor identification PathoGenetics Medium 20148114
2011 Missense mutations in the ARX homeodomain abolish DNA binding (measured by EMSA and ChIP after overexpression) and lead to loss of transcriptional repression of known ARX targets LMO1 and SHOX2; severity of DNA binding loss correlates with clinical phenotype severity. Luciferase reporter repression assay, EMSA, ChIP, quantitative RT-PCR of endogenous targets Human molecular genetics High 22194193
2012 DNA binding preference of ARX is influenced by amino acid sequences adjacent to the homeodomain; homeodomain mutations cause loss of DNA binding activity and loss of transcriptional repression; the P353L mutation retains partial DNA binding but all severe-phenotype mutations lose both binding and repression. EMSA with deletion and point mutants, luciferase transcriptional repression assay Neurogenetics High 22252899
2011 ARX directly regulates KDM5C (a chromatin remodeler mutated in XLID) through binding to a conserved noncoding regulatory element; polyalanine expansion mutations show decreased trans-activity and reduced binding to the KDM5C regulatory region; ARX knockout leads to dramatic Kdm5c mRNA downregulation, which inversely correlates with increased H3K4me3. ChIP, luciferase reporter, qRT-PCR, histone methylation assay in ARX KO neural stem cells American journal of human genetics High 23246292
2011 Chromatin immunoprecipitation combined with microarray identified ~1006 gene promoters bound by ARX in neuroblastoma cells and embryonic brain; ~24% of bound genes show expression changes upon ARX overexpression or knockdown, defining a large ARX transcriptional regulatory network. ChIP-chip (chromatin immunoprecipitation + microarray), mRNA expression microarray with Arx overexpression/knockdown PloS one High 21966449
2014 Lhx6 directly binds in vivo to an Arx enhancer to regulate Arx expression in MGE-derived interneurons; Arx re-expression in Lhx6-null MGE cells rescues cell-fate (but not laminar positioning) defects, establishing Arx as a direct downstream effector of Lhx6 in interneuron specification. In vivo ChIP at Arx enhancer, MGE complementation/transplantation rescue assay, conditional genetics Neuron High 24742460
2014 Arx, together with FoxA2, directly induces Shh expression in the floor plate by binding to the Shh floor plate enhancer SFPE2; FoxA2 activates Arx transcription, while Nkx2.2 (induced by Shh) suppresses Arx, forming a feedback loop. Arx functions here as a context-dependent transcriptional activator. Chick in ovo electroporation gain-of-function, Arx knockout mouse, enhancer binding assays Developmental biology High 24968361
2011 Islet-1 (Isl-1) activates Arx transcription in pancreatic alpha cells by binding two conserved noncoding regulatory regions (Re1 at +5.6–6.1 kb and Re2 at +23.6–24 kb) within the Arx locus; Isl-1 knockdown reduces Arx mRNA and Arx+ cell numbers in embryonic pancreas. ChIP localizing Isl-1 binding sites, cell line reporter assays (transfection with Re1/Re2-luciferase), Isl-1 KO embryo analysis, in vivo Isl-1 overexpression The Journal of biological chemistry High 21388963
2012 An ARX polyalanine expansion (GCG)7 knock-in does not affect GABAergic interneuron development or pyramidal cell migration, but causes increased excitatory input frequency and axonal arborization remodeling of hippocampal pyramidal neurons, suggesting epilepsy arises from glutamatergic network reorganization rather than interneuronopathy. Knock-in mouse, immunohistology, whole-cell electrophysiological recordings of IPSCs and EPSCs Cerebral cortex High 22628459
2013 Polyalanine expansion mutations in Arx cause a marked reduction in Arx protein abundance in developing forebrain without evidence of protein aggregates; the PA1 expansion shows more prominent loss of Lmo1 repression during neurogenesis stages than the PA2 expansion, potentially explaining phenotypic severity differences. Knock-in mouse models (Arx(GCG)7 and Arx432-455dup24), western blot, qRT-PCR of target gene expression Human molecular genetics High 24122442
2007 Arx is expressed downstream of myogenic bHLH genes in embryonic muscle, physically interacts with Mef2C (co-immunoprecipitation), and synergizes with Mef2C and MyoD to activate the Myogenin promoter and E-box reporters; Arx-deficient embryonic myoblasts show delayed differentiation in vivo and enhanced clonogenic capacity in vitro. Co-immunoprecipitation of Arx with Mef2C, transcriptional reporter assay, Arx knockout myoblast analysis Cell death and differentiation Medium 17932502
2014 Neonatal estradiol treatment prevents spasms and seizures in the Arx(GCG)10+7 mouse model; this treatment alters mRNA levels of three downstream Arx targets (Shox2, Ebf3, Lgi1) and restores depleted interneuron populations without increasing GABAergic synaptic density. Drug treatment of knock-in mouse model with EEG monitoring, interneuron quantification, qRT-PCR of ARX targets Science translational medicine Medium 24452264
2020 Postnatal Arx expression in parvalbumin interneurons (PVIs) regulates functional properties of these cells; conditional ablation of postnatal Arx specifically from PVIs causes hypoexcitability (intrinsic and synaptic), increased theta oscillations, occasional seizures, and anxiety, with genome-wide transcriptional changes in synaptic and extracellular matrix pathways. PV-specific conditional KO, EEG, whole-cell patch-clamp electrophysiology, FACS-sorted PVI genome-wide sequencing, behavioral analysis iScience High 33490907
2005 The C. elegans ARX ortholog alr-1 acts in a pathway with the LIM1 ortholog lin-11 to regulate chemosensory neuron development and is required for differentiation of GABAergic motoneuron subtypes, indicating conserved roles for ARX-family proteins in GABAergic neuron specification. Genetic epistasis in C. elegans, loss-of-function analysis with defined neuronal phenotypes Development (Cambridge, England) Medium 15790968

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nature genetics 525 12379852
2003 Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes & development 451 14561778
2002 ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Human molecular genetics 232 11971879
2004 Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Human mutation 231 14722918
2013 The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells. PLoS genetics 211 24204325
2011 Pancreatic β cell identity is maintained by DNA methylation-mediated repression of Arx. Developmental cell 209 21497756
2007 Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. The Journal of clinical investigation 203 17404619
2005 The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development (Cambridge, England) 175 15930104
2017 Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx. Cell metabolism 169 28215845
2009 Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females. Brain : a journal of neurology 158 19439424
2002 Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain & development 152 12142061
1997 Expression of a novel aristaless related homeobox gene 'Arx' in the vertebrate telencephalon, diencephalon and floor plate. Mechanisms of development 151 9256348
2009 A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment. The Journal of neuroscience : the official journal of the Society for Neuroscience 137 19587282
2007 A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). American journal of human genetics 132 17668384
2010 ARX spectrum disorders: making inroads into the molecular pathology. Human mutation 128 20506206
1997 Expression patterns of Brx1 (Rieg gene), Sonic hedgehog, Nkx2.2, Dlx1 and Arx during zona limitans intrathalamica and embryonic ventral lateral geniculate nuclear formation. Mechanisms of development 121 9347917
2008 Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 119 18923043
2007 Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology 114 17664401
2007 Inactivation of Arx, the murine ortholog of the X-linked lissencephaly with ambiguous genitalia gene, leads to severe disorganization of the ventral telencephalon with impaired neuronal migration and differentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 113 17460091
2008 Identification of Arx transcriptional targets in the developing basal forebrain. Human molecular genetics 109 18799476
2006 ARX: a gene for all seasons. Current opinion in genetics & development 108 16650978
2003 The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Current opinion in pediatrics 104 14631200
2014 Lhx6 directly regulates Arx and CXCR7 to determine cortical interneuron fate and laminar position. Neuron 100 24742460
2008 Cell-autonomous roles of ARX in cell proliferation and neuronal migration during corticogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 95 18509041
2005 Arx homeobox gene is essential for development of mouse olfactory system. Development (Cambridge, England) 94 15677725
2002 Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. American journal of medical genetics 93 12376946
2010 Mutations in ARX Result in Several Defects Involving GABAergic Neurons. Frontiers in cellular neuroscience 88 20300201
2004 Monogenic X-linked mental retardation: is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations. European journal of human genetics : EJHG 82 15319782
2012 The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice. PloS one 77 22570716
2002 X-linked myoclonic epilepsy with spasticity and intellectual disability: mutation in the homeobox gene ARX. Neurology 77 12177367
2004 Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons. Brain research. Molecular brain research 74 14992814
2004 A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. The Journal of cell biology 74 15533998
2013 Pancreatic α-cell specific deletion of mouse Arx leads to α-cell identity loss. PloS one 73 23785486
2009 Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice. Human molecular genetics 70 19605412
2006 The role of ARX in cortical development. The European journal of neuroscience 70 16519652
2004 Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons. Developmental dynamics : an official publication of the American Association of Anatomists 70 15376319
2003 ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology 63 12874405
2012 Arx is required for normal enteroendocrine cell development in mice and humans. Developmental biology 62 22387004
2002 Cell-wall proteinases PrtS and PrtB have a different role in Streptococcus thermophilus/Lactobacillus bulgaricus mixed cultures in milk. Microbiology (Reading, England) 62 12427933
2012 Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms. Current opinion in neurobiology 58 22565167
2009 The Xenopus Irx genes are essential for neural patterning and define the border between prethalamus and thalamus through mutual antagonism with the anterior repressors Fezf and Arx. Developmental biology 57 19268445
2014 Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome. Science translational medicine 56 24452264
2004 Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. Clinical genetics 55 15200506
2002 Human ARX gene: genomic characterization and expression. Molecular genetics and metabolism 55 12359145
2013 Aristaless related homeobox gene, Arx, is implicated in mouse fetal Leydig cell differentiation possibly through expressing in the progenitor cells. PloS one 54 23840809
2013 ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c. Cerebral cortex (New York, N.Y. : 1991) 54 23968833
2004 Screening of the ARX gene in 682 retarded males. European journal of human genetics : EJHG 49 15199382
2011 The fast milk acidifying phenotype of Streptococcus thermophilus can be acquired by natural transformation of the genomic island encoding the cell-envelope proteinase PrtS. Microbial cell factories 46 21995822
2011 Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiation. Frontiers in cellular neuroscience 46 22355284
2009 Arx acts as a regional key selector gene in the ventral telencephalon mainly through its transcriptional repression activity. Developmental biology 46 19627984
2016 Developmental interneuron subtype deficits after targeted loss of Arx. BMC neuroscience 40 27287386
2012 An epilepsy-related ARX polyalanine expansion modifies glutamatergic neurons excitability and morphology without affecting GABAergic neurons development. Cerebral cortex (New York, N.Y. : 1991) 40 22628459
2011 Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression. Developmental biology 40 21856296
2005 Screening of ARX in mental retardation families: Consequences for the strategy of molecular diagnosis. Neurogenetics 40 16235064
2012 A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. American journal of human genetics 38 23246292
2005 Regulation of chemosensory and GABAergic motor neuron development by the C. elegans Aristaless/Arx homolog alr-1. Development (Cambridge, England) 36 15790968
2012 Analysis of transcriptional codes for zebrafish dopaminergic neurons reveals essential functions of Arx and Isl1 in prethalamic dopaminergic neuron development. Developmental biology 34 22728160
2014 Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations. Cerebral cortex (New York, N.Y. : 1991) 33 24794919
2011 High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies. PloS one 33 21966449
2010 A novel ARX phenotype: rapid neurodegeneration with Ohtahara syndrome and a dyskinetic movement disorder. Developmental medicine and child neurology 33 19747203
2015 The Role of ARX in Human Pancreatic Endocrine Specification. PloS one 32 26633894
2011 Islet-1 regulates Arx transcription during pancreatic islet alpha-cell development. The Journal of biological chemistry 32 21388963
2010 Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division. PathoGenetics 32 20148114
2019 The maternal immune activation model uncovers a role for the Arx gene in GABAergic dysfunction in schizophrenia. Brain, behavior, and immunity 29 31175998
2010 Frameshift mutations of the ARX gene in familial Ohtahara syndrome. Epilepsia 29 20384723
2006 The ARX mutations: a frequent cause of X-linked mental retardation. American journal of medical genetics. Part A 29 16523516
2007 The homeobox gene Arx is a novel positive regulator of embryonic myogenesis. Cell death and differentiation 28 17932502
2019 Assessment of ARX expression, a novel biomarker for metastatic risk in pancreatic neuroendocrine tumors, in endoscopic ultrasound fine-needle aspiration. Diagnostic cytopathology 27 31846235
2011 ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia. American journal of medical genetics. Part A 27 21204215
2008 Expansion of the ARX spectrum. Clinical neurology and neurosurgery 27 18462864
2008 Combination of infantile spasms, non-epileptic seizures and complex movement disorder: a new case of ARX-related epilepsy. Epilepsy research 27 18468866
2005 The phenotypic spectrum of ARX mutations. Developmental medicine and child neurology 27 15707237
2009 Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X). European journal of human genetics : EJHG 26 19738637
2022 NanoDam identifies Homeobrain (ARX) and Scarecrow (NKX2.1) as conserved temporal factors in the Drosophila central brain and visual system. Developmental cell 25 35483359
2014 Arx together with FoxA2, regulates Shh floor plate expression. Developmental biology 25 24968361
2011 Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage. BMC developmental biology 25 21880149
1994 X-linked mental retardation with dystonic movements of the hands (PRTS): revisited. American journal of medical genetics 24 7943040
2011 A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females. Epilepsia 22 21426321
2011 Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene. Clinical genetics 22 21496008
2011 ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression. Human molecular genetics 22 22194193
2010 Familial Ohtahara syndrome due to a novel ARX gene mutation. American journal of medical genetics. Part A 22 21108397
2008 Disruption of the IQSEC2 transcript in a female with X;autosome translocation t(X;20)(p11.2;q11.2) and a phenotype resembling X-linked infantile spasms (ISSX) syndrome. Molecular medicine reports 22 21479374
2007 Mutation screening of the ARX gene in patients with autism. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 22 17044103
2022 Multifunctional Bioactive Scaffolds from ARX-g-(Zn@rGO)-HAp for Bone Tissue Engineering: In Vitro Antibacterial, Antitumor, and Biocompatibility Evaluations. ACS applied bio materials 21 36215135
2020 Streptococcus thermophilus growth in soya milk: Sucrose consumption, nitrogen metabolism, soya protein hydrolysis and role of the cell-wall protease PrtS. International journal of food microbiology 21 33065381
2013 Reduced polyalanine-expanded Arx mutant protein in developing mouse subpallium alters Lmo1 transcriptional regulation. Human molecular genetics 21 24122442
2010 Partial loss of pancreas endocrine and exocrine cells of human ARX-null mutation: consideration of pancreas differentiation. Differentiation; research in biological diversity 21 20538404
2005 XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless related homeobox) gene. BMC medical genetics 20 15850492
2005 Maternal mosaicism for mutations in the ARX gene in a family with X linked mental retardation. Human genetics 20 16078051
2003 X-linked mental retardation and epilepsy: pathogenetic significance of ARX mutations. Brain & development 19 12689693
2018 A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations. Human molecular genetics 18 29659809
2016 Redifferentiation of expanded human islet β cells by inhibition of ARX. Scientific reports 17 26856418
2012 Distinct DNA binding and transcriptional repression characteristics related to different ARX mutations. Neurogenetics 17 22252899
2006 Genotype-phenotype associations for ARX gene duplication in X-linked mental retardation. Neurology 17 17082467
2019 Arsenite Oxidation by a Newly Isolated Betaproteobacterium Possessing arx Genes and Diversity of the arx Gene Cluster in Bacterial Genomes. Frontiers in microbiology 16 31191509
2002 The Xenopus arx gene is expressed in the developing rostral forebrain. Development genes and evolution 16 12536326
2020 Postnatal Arx transcriptional activity regulates functional properties of PV interneurons. iScience 15 33490907
2017 ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmental deficit of calbindin-positive cortical GABAergic interneurons. Neuroscience 15 28627419
2016 Embryonic forebrain transcriptome of mice with polyalanine expansion mutations in the ARX homeobox gene. Human molecular genetics 15 27798109
2015 Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach. Molecular genetics & genomic medicine 15 26029707