ArticleHuman molecular genetics2018
A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 22 citations in OpenAlex.
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- Microglial EPOR Contribute to Sevoflurane-induced Developmental Fine Motor Deficits Through Synaptic Pruning in Mice.Neuroscience bulletin · 2024Article
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- Critical periods and Autism Spectrum Disorders, a role for sleep.Neurobiology of sleep and circadian rhythms · 2023Article
- Bypassing Mendel's First Law: Transmission Ratio Distortion in Mammals.International journal of molecular sciences · 2023Review
- Altered motor learning and coordination in mouse models of autism spectrum disorder.Frontiers in cellular neuroscience · 2023Review
- Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.Biomedicines · 2022Article
- Deregulation of microtubule organization and RNA metabolism in Arx models for lissencephaly and developmental epileptic encephalopathy.Human molecular genetics · 2022Article
- Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome.PLoS genetics · 2021Article
- Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models.Human molecular genetics · 2021Article
- PostnataliScience · 2021Article
- The potential of induced pluripotent stem cells for discriminating neurodevelopmental disorders.Stem cells translational medicine · 2021Review
- JNK signaling is required for proper tangential migration and laminar allocation of cortical interneurons.Development (Cambridge, England) · 2020Article
- NovelHuman genome variation · 2020Article
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Authors and funding
17 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans, among which the most frequent, a 24 bp duplication in the polyalanine tract 2 (c.428_451dup24), gives rise to intellectual disability, fine motor defects with or without epilepsy. To understand the functional consequences of this mutation, we generated a partially humanized mouse model carrying the c.428_451dup24 duplication (Arxdup24/0) that we characterized at the behavior, neurological and molecular level. Arxdup24/0 males presented with hyperactivity, enhanced stereotypies and altered contextual fear memory. In addition, Arxdup24/0 males had fine motor defects with alteration of reaching and grasping abilities. Transcriptome analysis of Arxdup24/0 forebrains at E15.5 showed a down-regulation of genes specific to interneurons and an up-regulation of genes normally not expressed in this cell type, suggesting abnormal interneuron development. Accordingly, interneuron migration was altered in the cortex and striatum between E15.5 and P0 with consequences in adults, illustrated by the defect in the inhibitory/excitatory balance in Arxdup24/0 basolateral amygdala. Altogether, we showed that the c.428_451dup24 mutation disrupts Arx function with a direct consequence on interneuron development, leading to hyperactivity and defects in precise motor movement control and associative memory. Interestingly, we highlighted striking similarities between the mouse phenotype and a cohort of 33 male patients with ARX c.428_451dup24, suggesting that this new mutant mouse line is a good model for understanding the pathophysiology and evaluation of treatment.
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