Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes

Abstract The gene KCNJ11 encodes Kir6.2 a major subunit of the ATP-sensitive potassium channel (KATP) expressed in both the pancreas and brain. Heterozygous gain of function mutations in KCNJ11 can cause neonatal diabetes mellitus (NDM). In addition, many patients exhibit neurological defects rangin...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Gokhan Dalgin, Andrew K. Tryba, Ashley P. Cohen, Soo-Young Park, Louis H. Philipson, Siri Atma W. Greeley, Alfredo J. Garcia
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/879668c1d1e34e7388085a487600bc5a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:879668c1d1e34e7388085a487600bc5a
record_format	dspace
spelling	oai:doaj.org-article:879668c1d1e34e7388085a487600bc5a2021-11-08T10:46:34ZDevelopmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes10.1038/s41598-021-00939-72045-2322https://doaj.org/article/879668c1d1e34e7388085a487600bc5a2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00939-7https://doaj.org/toc/2045-2322Abstract The gene KCNJ11 encodes Kir6.2 a major subunit of the ATP-sensitive potassium channel (KATP) expressed in both the pancreas and brain. Heterozygous gain of function mutations in KCNJ11 can cause neonatal diabetes mellitus (NDM). In addition, many patients exhibit neurological defects ranging from modest learning disorders to severe cognitive dysfunction and seizures. However, it remains unclear to what extent these neurological deficits are due to direct brain-specific activity of mutant KATP. We have generated cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) possessing the KCNJ11 mutation p.Val59Met (V59M) and from non-pathogenic/normal hiPSCs (i.e., control/WT). Control cerebral organoids developed neural networks that could generate stable synchronized bursting neuronal activity whereas those derived from V59M cerebral organoids showed reduced synchronization. Histocytochemical studies revealed a marked reduction in neurons localized to upper cortical layer-like structures in V59M cerebral organoids suggesting dysfunction in the development of cortical neuronal network. Examination of temporal transcriptional profiles of neural stem cell markers revealed an extended window of SOX2 expression in V59M cerebral organoids. Continuous treatment of V59M cerebral organoids with the KATP blocker tolbutamide partially rescued the neurodevelopmental differences. Our study demonstrates the utility of human cerebral organoids as an investigative platform for studying the effects of KCNJ11 mutations on neurophysiological outcome.Gokhan DalginAndrew K. TrybaAshley P. CohenSoo-Young ParkLouis H. PhilipsonSiri Atma W. GreeleyAlfredo J. GarciaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gokhan Dalgin Andrew K. Tryba Ashley P. Cohen Soo-Young Park Louis H. Philipson Siri Atma W. Greeley Alfredo J. Garcia Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes
description	Abstract The gene KCNJ11 encodes Kir6.2 a major subunit of the ATP-sensitive potassium channel (KATP) expressed in both the pancreas and brain. Heterozygous gain of function mutations in KCNJ11 can cause neonatal diabetes mellitus (NDM). In addition, many patients exhibit neurological defects ranging from modest learning disorders to severe cognitive dysfunction and seizures. However, it remains unclear to what extent these neurological deficits are due to direct brain-specific activity of mutant KATP. We have generated cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) possessing the KCNJ11 mutation p.Val59Met (V59M) and from non-pathogenic/normal hiPSCs (i.e., control/WT). Control cerebral organoids developed neural networks that could generate stable synchronized bursting neuronal activity whereas those derived from V59M cerebral organoids showed reduced synchronization. Histocytochemical studies revealed a marked reduction in neurons localized to upper cortical layer-like structures in V59M cerebral organoids suggesting dysfunction in the development of cortical neuronal network. Examination of temporal transcriptional profiles of neural stem cell markers revealed an extended window of SOX2 expression in V59M cerebral organoids. Continuous treatment of V59M cerebral organoids with the KATP blocker tolbutamide partially rescued the neurodevelopmental differences. Our study demonstrates the utility of human cerebral organoids as an investigative platform for studying the effects of KCNJ11 mutations on neurophysiological outcome.
format	article
author	Gokhan Dalgin Andrew K. Tryba Ashley P. Cohen Soo-Young Park Louis H. Philipson Siri Atma W. Greeley Alfredo J. Garcia
author_facet	Gokhan Dalgin Andrew K. Tryba Ashley P. Cohen Soo-Young Park Louis H. Philipson Siri Atma W. Greeley Alfredo J. Garcia
author_sort	Gokhan Dalgin
title	Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes
title_short	Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes
title_full	Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes
title_fullStr	Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes
title_full_unstemmed	Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes
title_sort	developmental defects and impaired network excitability in a cerebral organoid model of kcnj11 p.v59m-related neonatal diabetes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/879668c1d1e34e7388085a487600bc5a
work_keys_str_mv	AT gokhandalgin developmentaldefectsandimpairednetworkexcitabilityinacerebralorganoidmodelofkcnj11pv59mrelatedneonataldiabetes AT andrewktryba developmentaldefectsandimpairednetworkexcitabilityinacerebralorganoidmodelofkcnj11pv59mrelatedneonataldiabetes AT ashleypcohen developmentaldefectsandimpairednetworkexcitabilityinacerebralorganoidmodelofkcnj11pv59mrelatedneonataldiabetes AT sooyoungpark developmentaldefectsandimpairednetworkexcitabilityinacerebralorganoidmodelofkcnj11pv59mrelatedneonataldiabetes AT louishphilipson developmentaldefectsandimpairednetworkexcitabilityinacerebralorganoidmodelofkcnj11pv59mrelatedneonataldiabetes AT siriatmawgreeley developmentaldefectsandimpairednetworkexcitabilityinacerebralorganoidmodelofkcnj11pv59mrelatedneonataldiabetes AT alfredojgarcia developmentaldefectsandimpairednetworkexcitabilityinacerebralorganoidmodelofkcnj11pv59mrelatedneonataldiabetes
_version_	1718442635938496512

Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes

Ejemplares similares