{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T20:40:07Z","timestamp":1789332007689,"version":"build-2803163510"},"reference-count":48,"publisher":"The Company of Biologists","issue":"3","license":[{"start":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T00:00:00Z","timestamp":1612828800000},"content-version":"vor","delay-in-days":345,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS29709"],"award-info":[{"award-number":["NS29709"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002736","name":"Citizens United for Research in Epilepsy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002736","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001454","name":"American Epilepsy Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001454","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Blue Bird Circle Foundation for Pediatric Neurology Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>X-linked infantile spasms syndrome (ISSX) is a clinically devastating developmental epileptic encephalopathy with life-long impact. Arx(GCG)10+7, a mouse model of the most common triplet-repeat expansion mutation of ARX, exhibits neonatal spasms, electrographic phenotypes and abnormal migration of GABAergic interneuron subtypes. Neonatal presymptomatic treatment with 17\u03b2-estradiol (E2) in Arx(GCG)10+7 reduces spasms and modifies progression of epilepsy. Cortical pathology during this period, a crucial point for clinical intervention in ISSX, has largely been unexplored, and the pathogenic cellular defects that are targeted by early interventions are unknown. In the first postnatal week, we identified a transient wave of elevated apoptosis in Arx(GCG)10+7 mouse cortex that is non-Arx cell autonomous, since mutant Arx-immunoreactive (Arx+) cells are not preferentially impacted by cell death. NeuN+ (also known as Rbfox3) survival was also not impacted, suggesting a vulnerable subpopulation in the immature Arx(GCG)10+7 cortex. Inflammatory processes during this period might explain this transient elevation in apoptosis; however, transcriptomic and immunohistochemical profiling of several markers of inflammation revealed no innate immune activation in Arx(GCG)10+7 cortex. Neither neonatal E2 hormone therapy, nor ACTH(1-24), the frontline clinical therapy for ISSX, diminished the augmented apoptosis in Arx(GCG)10+7, but both rescued neocortical Arx+ cell density. Since early E2 treatment effectively prevents seizures in this model, enhanced apoptosis does not solely account for the seizure phenotype, but may contribute to other aberrant brain function in ISSX. However, since both hormone therapies, E2 and ACTH(1-24), elevate the density of cortical Arx+-interneurons, their early therapeutic role in other neurological disorders hallmarked by interneuronopathy should be explored.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/dmm.042515","type":"journal-article","created":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T14:58:18Z","timestamp":1581087498000},"source":"Crossref","is-referenced-by-count":18,"title":["<i>Arx<\/i> expansion mutation perturbs cortical development by augmenting apoptosis without activating innate immunity in a mouse model of X-linked infantile spasms syndrome"],"prefix":"10.1242","volume":"13","author":[{"given":"Meagan S.","family":"Siehr","sequence":"first","affiliation":[{"name":"Baylor College of Medicine 1 Developmental Neurogenetics Laboratory, Department of Neurology , , One Baylor Plaza, Houston, TX 77030 , USA"},{"name":"Baylor College of Medicine 2 Molecular and Human Genetics , , One Baylor Plaza, Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory A.","family":"Massey","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine 1 Developmental Neurogenetics Laboratory, Department of Neurology , , One Baylor Plaza, Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2887-0839","authenticated-orcid":false,"given":"Jeffrey L.","family":"Noebels","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine 1 Developmental Neurogenetics Laboratory, Department of Neurology , , One Baylor Plaza, Houston, TX 77030 , USA"},{"name":"Baylor College of Medicine 2 Molecular and Human Genetics , , One Baylor Plaza, Houston, TX 77030 , USA"},{"name":"Baylor College of Medicine 3 Neuroscience , , One Baylor Plaza, Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,3,30]]},"reference":[{"key":"2024061302382898100_DMM042515C1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.siny.2018.01.003","article-title":"Neonatal epilepsy genetics","volume":"23","author":"Axeen","year":"2018","journal-title":"Semin. Fetal. Neonatal. Med."},{"key":"2024061302382898100_DMM042515C2","doi-asserted-by":"publisher","first-page":"100787","DOI":"10.1016\/j.yfrne.2019.100787","article-title":"Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences","volume":"55","author":"Azcoitia","year":"2019","journal-title":"Front. Neuroendocrinol."},{"key":"2024061302382898100_DMM042515C3","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1093\/cercor\/bhs138","article-title":"An epilepsy-related ARX polyalanine expansion modifies glutamatergic neurons excitability and morphology without affecting GABAergic neurons development","volume":"23","author":"Beguin","year":"2013","journal-title":"Cereb. Cortex"},{"key":"2024061302382898100_DMM042515C4","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1093\/hmg\/11.8.981","article-title":"ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation","volume":"11","author":"Bienvenu","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2024061302382898100_DMM042515C5","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1111\/epi.13434","article-title":"Estradiol does not affect spasms in the betamethasone-NMDA rat model of infantile spasms","volume":"57","author":"Chachua","year":"2016","journal-title":"Epilepsia"},{"key":"2024061302382898100_DMM042515C6","doi-asserted-by":"publisher","first-page":"10674","DOI":"10.1523\/JNEUROSCI.1283-08.2008","article-title":"Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons","volume":"28","author":"Colasante","year":"2008","journal-title":"J. Neurosci."},{"key":"2024061302382898100_DMM042515C7","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1093\/cercor\/bht222","article-title":"ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c","volume":"25","author":"Colasante","year":"2015","journal-title":"Cereb. Cortex"},{"key":"2024061302382898100_DMM042515C8","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1002\/dvdy.20164","article-title":"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","volume":"231","author":"Colombo","year":"2004","journal-title":"Dev. Dyn."},{"key":"2024061302382898100_DMM042515C9","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13229-018-0199-3","article-title":"17-beta estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms","volume":"9","author":"Filice","year":"2018","journal-title":"Mol. Autism"},{"key":"2024061302382898100_DMM042515C10","doi-asserted-by":"publisher","first-page":"28","DOI":"10.3389\/fncel.2011.00028","article-title":"Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiation","volume":"5","author":"Friocourt","year":"2011","journal-title":"Front. Cell Neurosci."},{"key":"2024061302382898100_DMM042515C11","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1111\/j.1460-9568.2006.04629.x","article-title":"The role of ARX in cortical development","volume":"23","author":"Friocourt","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"2024061302382898100_DMM042515C12","doi-asserted-by":"publisher","first-page":"5794","DOI":"10.1523\/JNEUROSCI.1067-08.2008","article-title":"Cell-autonomous roles of ARX in cell proliferation and neuronal migration during corticogenesis","volume":"28","author":"Friocourt","year":"2008","journal-title":"J. Neurosci."},{"key":"2024061302382898100_DMM042515C13","doi-asserted-by":"publisher","first-page":"3740","DOI":"10.1093\/hmg\/ddn271","article-title":"Identification of Arx transcriptional targets in the developing basal forebrain","volume":"17","author":"Fulp","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"2024061302382898100_DMM042515C14","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/nrneurol.2015.13","article-title":"The role of inflammation in perinatal brain injury","volume":"11","author":"Hagberg","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"2024061302382898100_DMM042515C15","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.spen.2016.06.001","article-title":"Current and emerging therapies of severe epileptic encephalopathies","volume":"23","author":"Hani","year":"2016","journal-title":"Semin. Pediatr. Neurol."},{"key":"2024061302382898100_DMM042515C16","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1146\/annurev-neuro-072116-031250","article-title":"Catastrophic epilepsies of childhood","volume":"40","author":"Howard","year":"2017","journal-title":"Annu. Rev. Neurosci."},{"key":"2024061302382898100_DMM042515C17","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1097\/WCO.0000000000000535","article-title":"The epileptic encephalopathy jungle - from Dr West to the concepts of aetiology-related and developmental encephalopathies","volume":"31","author":"Kalser","year":"2018","journal-title":"Curr. Opin. Neurol."},{"key":"2024061302382898100_DMM042515C18","doi-asserted-by":"publisher","first-page":"181","DOI":"10.3389\/fnins.2015.00181","article-title":"Genotype-phenotype correlation in neuronal migration disorders and cortical dysplasias","volume":"9","author":"Kato","year":"2015","journal-title":"Front. Neurosci."},{"key":"2024061302382898100_DMM042515C19","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1177\/08830738050200042001","article-title":"X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, \u201cinterneuronopathy\u201d","volume":"20","author":"Kato","year":"2005","journal-title":"J. Child Neurol."},{"key":"2024061302382898100_DMM042515C20","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/humu.10310","article-title":"Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation","volume":"23","author":"Kato","year":"2004","journal-title":"Hum. Mutat."},{"key":"2024061302382898100_DMM042515C21","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s11910-018-0832-8","article-title":"Infantile spasms-have we made progress?","volume":"18","author":"Kelley","year":"2018","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"2024061302382898100_DMM042515C22","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/ng1009","article-title":"Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans","volume":"32","author":"Kitamura","year":"2002","journal-title":"Nat. Genet."},{"key":"2024061302382898100_DMM042515C23","doi-asserted-by":"publisher","first-page":"3708","DOI":"10.1093\/hmg\/ddp318","article-title":"Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice","volume":"18","author":"Kitamura","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2024061302382898100_DMM042515C24","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1093\/hmg\/ddt503","article-title":"Reduced polyalanine-expanded Arx mutant protein in developing mouse subpallium alters Lmo1 transcriptional regulation","volume":"23","author":"Lee","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"2024061302382898100_DMM042515C25","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.neuroscience.2017.06.010","article-title":"ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmental deficit of calbindin-positive cortical GABAergic interneurons","volume":"357","author":"Lee","year":"2017","journal-title":"Neuroscience"},{"key":"2024061302382898100_DMM042515C26","doi-asserted-by":"publisher","first-page":"5433","DOI":"10.1093\/hmg\/ddw360","article-title":"Embryonic forebrain transcriptome of mice with polyalanine expansion mutations in the ARX homeobox gene","volume":"25","author":"Mattiske","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2024061302382898100_DMM042515C27","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/S1474-4422(15)00250-1","article-title":"The genetic landscape of the epileptic encephalopathies of infancy and childhood","volume":"15","author":"McTague","year":"2016","journal-title":"Lancet Neurol."},{"key":"2024061302382898100_DMM042515C28","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1083\/jcb.200408091","article-title":"A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death","volume":"167","author":"Nasrallah","year":"2004","journal-title":"J. Cell Biol."},{"key":"2024061302382898100_DMM042515C29","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1093\/hmg\/ddr538","article-title":"Differential effects of a polyalanine tract expansion in Arx on neural development and gene expression","volume":"21","author":"Nasrallah","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2024061302382898100_DMM042515C30","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1016\/j.conb.2012.04.006","article-title":"Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms","volume":"22","author":"Olivetti","year":"2012","journal-title":"Curr. Opin. Neurobiol."},{"key":"2024061302382898100_DMM042515C31","doi-asserted-by":"publisher","first-page":"220ra12","DOI":"10.1126\/scitranslmed.3007231","article-title":"Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome","volume":"6","author":"Olivetti","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"2024061302382898100_DMM042515C32","doi-asserted-by":"publisher","first-page":"7378","DOI":"10.1523\/JNEUROSCI.0478-18.2018","article-title":"Estrogen treatment reverses prematurity-induced disruption in cortical interneuron population","volume":"38","author":"Panda","year":"2018","journal-title":"J. Neurosci."},{"key":"2024061302382898100_DMM042515C33","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/s13311-014-0265-2","article-title":"Mechanisms of epileptogenesis in pediatric epileptic syndromes: Rasmussen encephalitis, infantile spasms, and febrile infection-related epilepsy syndrome (FIRES)","volume":"11","author":"Pardo","year":"2014","journal-title":"Neurotherapeutics"},{"key":"2024061302382898100_DMM042515C34","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.molbrainres.2003.11.021","article-title":"Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons","volume":"122","author":"Poirier","year":"2004","journal-title":"Brain Res. Mol. Brain Res."},{"key":"2024061302382898100_DMM042515C35","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/sj.cdd.4400476","article-title":"Emerging roles of caspase-3 in apoptosis","volume":"6","author":"Porter","year":"1999","journal-title":"Cell Death Differ."},{"key":"2024061302382898100_DMM042515C36","doi-asserted-by":"publisher","first-page":"8752","DOI":"10.1523\/JNEUROSCI.0915-09.2009","article-title":"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","volume":"29","author":"Price","year":"2009","journal-title":"J. Neurosci."},{"key":"2024061302382898100_DMM042515C37","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1016\/j.celrep.2018.01.007","article-title":"Activity regulates cell death within cortical interneurons through a calcineurin-dependent mechanism","volume":"22","author":"Priya","year":"2018","journal-title":"Cell Rep."},{"key":"2024061302382898100_DMM042515C38","doi-asserted-by":"publisher","first-page":"e25181","DOI":"10.1371\/journal.pone.0025181","article-title":"High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies","volume":"6","author":"Quill\u00e9","year":"2011","journal-title":"PLoS ONE"},{"key":"2024061302382898100_DMM042515C39","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/bs.apcsb.2017.01.005","article-title":"Inflammation in Epileptic Encephalopathies","volume":"108","author":"Shandra","year":"2017","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"2024061302382898100_DMM042515C40","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1097\/00008480-200312000-00004","article-title":"The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes","volume":"15","author":"Sherr","year":"2003","journal-title":"Curr. Opin. Pediatr."},{"key":"2024061302382898100_DMM042515C41","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1002\/humu.21288","article-title":"ARX spectrum disorders: making inroads into the molecular pathology","volume":"31","author":"Shoubridge","year":"2010","journal-title":"Hum. Mutat."},{"key":"2024061302382898100_DMM042515C42","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1097\/WNF.0000000000000200","article-title":"Efficacy of treatments for infantile spasms: a systematic review","volume":"40","author":"Song","year":"2017","journal-title":"Clin. Neuropharmacol."},{"key":"2024061302382898100_DMM042515C43","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nature11523","article-title":"Intrinsically determined cell death of developing cortical interneurons","volume":"491","author":"Southwell","year":"2012","journal-title":"Nature"},{"key":"2024061302382898100_DMM042515C44","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1186\/1471-2105-6-225","article-title":"Pathway level analysis of gene expression using singular value decomposition","volume":"6","author":"Tomfohr","year":"2005","journal-title":"BMC Bioinformatics"},{"key":"2024061302382898100_DMM042515C45","doi-asserted-by":"publisher","first-page":"e78741","DOI":"10.1371\/journal.pone.0078741","article-title":"Arx polyalanine expansion in mice leads to reduced pancreatic \u03b1-cell specification and increased \u03b1-cell death","volume":"8","author":"Wilcox","year":"2013","journal-title":"PLoS ONE"},{"key":"2024061302382898100_DMM042515C46","doi-asserted-by":"publisher","first-page":"e66214","DOI":"10.1371\/journal.pone.0066214","article-title":"Pancreatic alpha-cell specific deletion of mouse Arx leads to \u03b1-cell identity loss","volume":"8","author":"Wilcox","year":"2013","journal-title":"PLoS ONE"},{"key":"2024061302382898100_DMM042515C47","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.tins.2015.08.002","article-title":"Priming the inflammatory pump of the CNS after traumatic brain injury","volume":"38","author":"Witcher","year":"2015","journal-title":"Trends Neurosci."},{"key":"2024061302382898100_DMM042515C48","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1146\/annurev-cellbio-100818-125204","article-title":"Developmental cell death in the cerebral cortex","volume":"35","author":"Wong","year":"2019","journal-title":"Annu. Rev. Cell Dev. Biol."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dmm.042515","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.042515\/3484743\/dmm042515.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.042515\/2065723\/dmm_042515v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.042515\/3484743\/dmm042515.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T02:38:55Z","timestamp":1718246335000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/13\/3\/dmm042515\/225236\/Arx-expansion-mutation-perturbs-cortical"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,1]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,3,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.042515","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2020,3,1]]},"article-number":"dmm042515"}}