Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs
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Published:2022-11-10
Issue:22
Volume:23
Page:13861
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Kim BumsooORCID,
Koh Yongjun,
Do Hyunsu,
Ju Younghee,
Choi Jong BinORCID,
Cho Gahyang,
Yoo Han-Wook,
Lee Beom HeeORCID,
Han JinjuORCID,
Park Jong-Eun,
Han Yong-Mahn
Abstract
Noonan syndrome (NS) is a genetic disorder mainly caused by gain-of-function mutations in Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Although diverse neurological manifestations are commonly diagnosed in NS patients, the mechanisms as to how SHP2 mutations induce the neurodevelopmental defects associated with NS remain elusive. Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs). Although NS-COs develop normally in their appearance, single-cell transcriptomic analysis revealed an increase in the EN population and overexpression of cortical layer markers in NS-COs. Surprisingly, the EN subpopulation co-expressing the upper layer marker SATB2 and the deep layer maker CTIP2 was enriched in NS-COs during cortical development. In parallel with the developmental disruptions, NS-COs also exhibited reduced synaptic connectivity. Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity contribute to the neurological manifestations of NS.
Funder
Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science and ICT
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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