Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons.

Autor: Runge K; INMED, INSERM, Aix-Marseille University, Marseille, France., Mathieu R; INMED, INSERM, Aix-Marseille University, Marseille, France., Bugeon S; IBDM, Aix-Marseille University, CNRS, UMR, Marseille, France., Lafi S; INMED, INSERM, Aix-Marseille University, Marseille, France.; IBDM, Aix-Marseille University, CNRS, UMR, Marseille, France., Beurrier C; IBDM, Aix-Marseille University, CNRS, UMR, Marseille, France., Sahu S; INMED, INSERM, Aix-Marseille University, Marseille, France., Schaller F; INMED, INSERM, Aix-Marseille University, Marseille, France., Loubat A; INMED, INSERM, Aix-Marseille University, Marseille, France., Herault L; TAGC INSERM U1090, Aix-Marseille University, Marseille, France., Gaillard S; Phenotype Expertise, 5 Boulevard du Maréchal Koenig, Marseille, France., Pallesi-Pocachard E; INMED, INSERM, Aix-Marseille University, Marseille, France., Montheil A; INMED, INSERM, Aix-Marseille University, Marseille, France., Bosio A; Miltenyi Biotec, Bergisch-Gladbach, Germany., Rosenfeld JA; Baylor College of Medicine, Houston, TX, USA., Hudson E; Cook Children's Clinical Genetics, Fort Worth, TX, USA., Lindstrom K; Division of genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, USA., Mercimek-Andrews S; Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada., Jeffries L; Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA., van Haeringen A; Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands., Vanakker O; Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium., Van Hecke A; Department of Neurology, Queen Fabiola Children's University Hospital, Brussels, Belgium.; Université Libre de Bruxelles (ULB), Brussels, Belgium., Amrom D; Department of Neurology, Queen Fabiola Children's University Hospital, Brussels, Belgium.; Université Libre de Bruxelles (ULB), Brussels, Belgium.; Neuropediatric Unit, Kannerklinik, Centre Hospitalier de Luxembourg, Luxembourg, Grand-Duchy of Luxembourg, Luxembourg, Luxembourg., Küry S; Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes, France.; INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes, France., Ratner C; Hackensack University Medical Center, Hackensack, NJ, USA., Jethva R; Hackensack University Medical Center, Hackensack, NJ, USA., Gamble C; Cook Children's Clinical Genetics, Fort Worth, TX, USA., Jacq B; IBDM, Aix-Marseille University, CNRS, UMR, Marseille, France., Fasano L; IBDM, Aix-Marseille University, CNRS, UMR, Marseille, France., Santpere G; Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA., Lorente-Galdos B; Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA., Sestan N; Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA., Gelot A; Trousseau Hospital, Paris, France., Giacuzz S; Trousseau Hospital, Paris, France., Goebbels S; Max-Planck-Institute of Experimental Medicine, Goettingen, Germany., Represa A; INMED, INSERM, Aix-Marseille University, Marseille, France., Cardoso C; INMED, INSERM, Aix-Marseille University, Marseille, France., Cremer H; IBDM, Aix-Marseille University, CNRS, UMR, Marseille, France., de Chevigny A; INMED, INSERM, Aix-Marseille University, Marseille, France. antoine.de-chevigny@inserm.fr.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2021 Nov; Vol. 26 (11), pp. 6125-6148. Date of Electronic Publication: 2021 Jun 29.
DOI: 10.1038/s41380-021-01179-x
Abstrakt: While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.
(© 2021. The Author(s).)
Databáze: MEDLINE
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