SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice

SHANK2 (ProSAP1) is a postsynaptic scaffolding protein of excitatory synapses in the central nervous system and implicated in the development of autism spectrum disorders (ASD). Patients with mutations in SHANK2 show autism-like behaviors, developmental delay, and intellectual disability. We generat...

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Autores principales:	Anne-Kathrin Lutz, Andrea Pérez Arévalo, Valentin Ioannidis, Nadine Stirmlinger, Maria Demestre, Richard Delorme, Thomas Bourgeron, Tobias M. Boeckers
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	SHANK2 hiPSCs ERK1/2 neurodevelopment ASD Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/62de73e79ade401bb205c8be84ad16a1
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spelling	oai:doaj.org-article:62de73e79ade401bb205c8be84ad16a12021-12-01T08:00:15ZSHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice1662-509910.3389/fnmol.2021.773571https://doaj.org/article/62de73e79ade401bb205c8be84ad16a12021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnmol.2021.773571/fullhttps://doaj.org/toc/1662-5099SHANK2 (ProSAP1) is a postsynaptic scaffolding protein of excitatory synapses in the central nervous system and implicated in the development of autism spectrum disorders (ASD). Patients with mutations in SHANK2 show autism-like behaviors, developmental delay, and intellectual disability. We generated human induced pluripotent stem cells (hiPSC) from a patient carrying a heterozygous deletion of SHANK2 and from the unaffected parents. In patient hiPSCs and derived neurons SHANK2 mRNA and protein expression was reduced. During neuronal maturation, a reduction in growth cone size and a transient increase in neuronal soma size were observed. Neuronal proliferation was increased, and apoptosis was decreased in young and mature neurons. Additionally, mature patient hiPSC-derived neurons showed dysregulated excitatory signaling and a decrease of a broad range of signaling molecules of the ERK-MAP kinase pathway. These findings could be confirmed in brain samples from Shank2(−/−) mice, which also showed decreased mGluR5 and phospho-ERK1/2 expression. Our study broadens the current knowledge of SHANK2-related ASD. We highlight the importance of excitatory-inhibitory balance and mGluR5 dysregulation with disturbed downstream ERK1/2 signaling in ASD, which provides possible future therapeutic strategies for SHANK2-related ASD.Anne-Kathrin LutzAndrea Pérez ArévaloValentin IoannidisNadine StirmlingerMaria DemestreRichard DelormeThomas BourgeronTobias M. BoeckersTobias M. BoeckersFrontiers Media S.A.articleSHANK2hiPSCsERK1/2neurodevelopmentASDNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Molecular Neuroscience, Vol 14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	SHANK2 hiPSCs ERK1/2 neurodevelopment ASD Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	SHANK2 hiPSCs ERK1/2 neurodevelopment ASD Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Anne-Kathrin Lutz Andrea Pérez Arévalo Valentin Ioannidis Nadine Stirmlinger Maria Demestre Richard Delorme Thomas Bourgeron Tobias M. Boeckers Tobias M. Boeckers SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice
description	SHANK2 (ProSAP1) is a postsynaptic scaffolding protein of excitatory synapses in the central nervous system and implicated in the development of autism spectrum disorders (ASD). Patients with mutations in SHANK2 show autism-like behaviors, developmental delay, and intellectual disability. We generated human induced pluripotent stem cells (hiPSC) from a patient carrying a heterozygous deletion of SHANK2 and from the unaffected parents. In patient hiPSCs and derived neurons SHANK2 mRNA and protein expression was reduced. During neuronal maturation, a reduction in growth cone size and a transient increase in neuronal soma size were observed. Neuronal proliferation was increased, and apoptosis was decreased in young and mature neurons. Additionally, mature patient hiPSC-derived neurons showed dysregulated excitatory signaling and a decrease of a broad range of signaling molecules of the ERK-MAP kinase pathway. These findings could be confirmed in brain samples from Shank2(−/−) mice, which also showed decreased mGluR5 and phospho-ERK1/2 expression. Our study broadens the current knowledge of SHANK2-related ASD. We highlight the importance of excitatory-inhibitory balance and mGluR5 dysregulation with disturbed downstream ERK1/2 signaling in ASD, which provides possible future therapeutic strategies for SHANK2-related ASD.
format	article
author	Anne-Kathrin Lutz Andrea Pérez Arévalo Valentin Ioannidis Nadine Stirmlinger Maria Demestre Richard Delorme Thomas Bourgeron Tobias M. Boeckers Tobias M. Boeckers
author_facet	Anne-Kathrin Lutz Andrea Pérez Arévalo Valentin Ioannidis Nadine Stirmlinger Maria Demestre Richard Delorme Thomas Bourgeron Tobias M. Boeckers Tobias M. Boeckers
author_sort	Anne-Kathrin Lutz
title	SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice
title_short	SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice
title_full	SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice
title_fullStr	SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice
title_full_unstemmed	SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice
title_sort	shank2 mutations result in dysregulation of the erk1/2 pathway in human induced pluripotent stem cells-derived neurons and shank2(−/−) mice
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/62de73e79ade401bb205c8be84ad16a1
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SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice

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