Academic Journal
A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations
| العنوان: | A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations |
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| المؤلفون: | Dubos, Aline, Meziane, Hamid, Iacono, Giovanni, Curie, Aurore, Riet, Fabrice, Martin, Christelle, Loaec, Nadège, Birling, Marie-Christine, Selloum, Mohammed, Normand, Elisabeth, Pavlovic, Guillaume, Sorg, Tania, Stunnenberg, Henk G., Chelly, Jamel, Humeau, Yann, Friocourt, Gaëlle, Herault, Yann |
| المساهمون: | Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut Clinique de la Souris (ICS), Radboud University Nijmegen, Hôpital Femme Mère Enfant CHU - HCL (HFME), Hospices Civils de Lyon (HCL), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure de Lyon (ENS de Lyon), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience / Institut interdisciplinaire de neurosciences Bordeaux (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Etablissement Français du Sang Bretagne, EFS, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Morvan Brest, Nouvel Hôpital Civil de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010) |
| المصدر: | ISSN: 0964-6906. |
| بيانات النشر: | CCSD Oxford University Press (OUP) |
| سنة النشر: | 2018 |
| المجموعة: | HAL Lyon 1 (University Claude Bernard Lyon 1) |
| مصطلحات موضوعية: | [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/29659809; PUBMED: 29659809; PUBMEDCENTRAL: PMC5985730 |
| DOI: | 10.1093/hmg/ddy122 |
| الاتاحة: | https://hal.science/hal-03664342 https://hal.science/hal-03664342v1/document https://hal.science/hal-03664342v1/file/ddy122.pdf https://doi.org/10.1093/hmg/ddy122 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.BF2FE318 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/hmg/ddy122 |
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