A chimeric mouse model to study human iPSC-derived neurons: the case of a truncating SHANK3 mutation

Autor: Jean-Pierre Bourgeois, Nathalie Lemière, Stéphanie Pons, Isabelle Cloëz-Tayarani, Uwe Maskos, Marta Balkota, Aline Vitrac, Célia Raïs, Thomas Bourgeron
Přispěvatelé: Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Collège doctoral [Sorbonne universités], Sorbonne Université (SU), The authors are thankful to the Clinical Investigation Center of Robert Debré hospital for assistance with patient recruitment and to Dr. Alexandra Benchoua who performed the initial iPSC reprogramming. The French Ministry of Education and the LabEx BioPsy provided the funding for AV’s PhD. Other funding for this study were provided by grants from the French National Research Agency ANR (ANR-13-SAMA-0006, SynDivAutism), the Bettencourt-Schueller Foundation, the Cognacq Jay Foundation, the Fondamental Foundation and the Fondation pour la Recherche Médicale 'FRM Equipe 2019'. We gratefully acknowledge the UtechS Photonic Bioimaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging, ANR-10-INSB-04, Investments for the future). We also gratefully acknowledge the help of Image Analysis Hub of the Institut Pasteur for this work. NINDS Repository sample numbers corresponding to the sample used in this study is GM04603 ('4603')., ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Collège Doctoral
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Scientific Reports
Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.13315. ⟨10.1038/s41598-020-70056-4⟩
Scientific Reports, 2020, 10 (1), pp.13315. ⟨10.1038/s41598-020-70056-4⟩
Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
ISSN: 2045-2322
Popis: Using human induced pluripotent stem cells (iPSC), recent studies have shown that the events underlying autism spectrum disorders (ASD) can occur during neonatal development. We previously analyzed the iPSC-derived pyramidal cortical neurons of a subset of patients with ASD carrying de novo heterozygous mutations in postsynaptic SHANK3 protein, in culture. We reported altered spinogenesis of those neurons. The transplantation of human iPSC-derived neuronal precursors into mouse brain represents a novel option for in vivo analysis of mutations affecting the human brain. In this study, we transplanted the neuronal precursor cells (NPC) into the cortex of newborn mice to analyze their integration and maturation at early stages of development and studied axonal projections of transplanted human neurons into adult mouse brain. We then co-transplanted NPC from a control individual and from a patient carrying a de novo heterozygous SHANK3 mutation. We observed a reduction in cell soma size of selective neuronal categories and in axonal projections at 30 days post-transplantation. In contrast to previous in vitro studies, we did not observe any alteration in spinogenesis at this early age. The humanized chimeric mouse models offer the means to analyze ASD-associated mutations further and provide the opportunity to visualize phenotypes in vivo.
Databáze: OpenAIRE
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