Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons
SHANK3 mutations, including de novo deletions, have been associated with autism spectrum disorders (ASD). However, the effects of SHANK3 loss of function on neurodevelopment remain poorly understood. Here we generated human induced pluripotent stem cells (iPSC) in vitro, followed by neuro-differenti...
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Format: | Article |
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Frontiers Media S.A.
2019-03-01
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Series: | Frontiers in Neuroanatomy |
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Online Access: | https://www.frontiersin.org/article/10.3389/fnana.2019.00023/full |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Guanqun Huang Guanqun Huang Shuting Chen Xiaoxia Chen Jiajun Zheng Zhuoran Xu Abolfazl Doostparast Torshizi Abolfazl Doostparast Torshizi Siyi Gong Qingpei Chen Xiaokuang Ma Jiandong Yu Libing Zhou Shenfeng Qiu Kai Wang Kai Wang Lingling Shi Lingling Shi |
spellingShingle |
Guanqun Huang Guanqun Huang Shuting Chen Xiaoxia Chen Jiajun Zheng Zhuoran Xu Abolfazl Doostparast Torshizi Abolfazl Doostparast Torshizi Siyi Gong Qingpei Chen Xiaokuang Ma Jiandong Yu Libing Zhou Shenfeng Qiu Kai Wang Kai Wang Lingling Shi Lingling Shi Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons Frontiers in Neuroanatomy induced pluripotent stem cells neural stem cells SHANK3 electrophysiology RNA-Seq autism |
author_facet |
Guanqun Huang Guanqun Huang Shuting Chen Xiaoxia Chen Jiajun Zheng Zhuoran Xu Abolfazl Doostparast Torshizi Abolfazl Doostparast Torshizi Siyi Gong Qingpei Chen Xiaokuang Ma Jiandong Yu Libing Zhou Shenfeng Qiu Kai Wang Kai Wang Lingling Shi Lingling Shi |
author_sort |
Guanqun Huang |
title |
Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons |
title_short |
Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons |
title_full |
Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons |
title_fullStr |
Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons |
title_full_unstemmed |
Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons |
title_sort |
uncovering the functional link between shank3 deletions and deficiency in neurodevelopment using ipsc-derived human neurons |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroanatomy |
issn |
1662-5129 |
publishDate |
2019-03-01 |
description |
SHANK3 mutations, including de novo deletions, have been associated with autism spectrum disorders (ASD). However, the effects of SHANK3 loss of function on neurodevelopment remain poorly understood. Here we generated human induced pluripotent stem cells (iPSC) in vitro, followed by neuro-differentiation and lentivirus-mediated shRNA expression to evaluate how SHANK3 knockdown affects the in vitro neurodevelopmental process at multiple time points (up to 4 weeks). We found that SHANK3 knockdown impaired both early stage of neuronal development and mature neuronal function, as demonstrated by a reduction in neuronal soma size, growth cone area, neurite length and branch numbers. Notably, electrophysiology analyses showed defects in excitatory and inhibitory synaptic transmission. Furthermore, transcriptome analyses revealed that multiple biological pathways related to neuron projection, motility and regulation of neurogenesis were disrupted in cells with SHANK3 knockdown. In conclusion, utilizing a human iPSC-based neural induction model, this study presented combined morphological, electrophysiological and transcription evidence that support that SHANK3 as an intrinsic, cell autonomous factor that controls cellular function development in human neurons. |
topic |
induced pluripotent stem cells neural stem cells SHANK3 electrophysiology RNA-Seq autism |
url |
https://www.frontiersin.org/article/10.3389/fnana.2019.00023/full |
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doaj-ad0d3c36eb624333894f1743b9b65e422020-11-25T00:13:21ZengFrontiers Media S.A.Frontiers in Neuroanatomy1662-51292019-03-011310.3389/fnana.2019.00023403326Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human NeuronsGuanqun Huang0Guanqun Huang1Shuting Chen2Xiaoxia Chen3Jiajun Zheng4Zhuoran Xu5Abolfazl Doostparast Torshizi6Abolfazl Doostparast Torshizi7Siyi Gong8Qingpei Chen9Xiaokuang Ma10Jiandong Yu11Libing Zhou12Shenfeng Qiu13Kai Wang14Kai Wang15Lingling Shi16Lingling Shi17Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaDepartment of Basic Medical Sciences, College of Medicine – Phoenix, The University of Arizona, Phoenix, AZ, United StatesGuangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaGuangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaGuangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaDepartment of Biomedical Informatics, Columbia University, New York, NY, United StatesDepartment of Biomedical Informatics, Columbia University, New York, NY, United StatesChildren’s Hospital of Philadelphia, Philadelphia, PA, United StatesGuangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaGuangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaDepartment of Basic Medical Sciences, College of Medicine – Phoenix, The University of Arizona, Phoenix, AZ, United StatesGuangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaGuangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaDepartment of Basic Medical Sciences, College of Medicine – Phoenix, The University of Arizona, Phoenix, AZ, United StatesDepartment of Biomedical Informatics, Columbia University, New York, NY, United StatesChildren’s Hospital of Philadelphia, Philadelphia, PA, United StatesGuangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, ChinaCo-innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaSHANK3 mutations, including de novo deletions, have been associated with autism spectrum disorders (ASD). However, the effects of SHANK3 loss of function on neurodevelopment remain poorly understood. Here we generated human induced pluripotent stem cells (iPSC) in vitro, followed by neuro-differentiation and lentivirus-mediated shRNA expression to evaluate how SHANK3 knockdown affects the in vitro neurodevelopmental process at multiple time points (up to 4 weeks). We found that SHANK3 knockdown impaired both early stage of neuronal development and mature neuronal function, as demonstrated by a reduction in neuronal soma size, growth cone area, neurite length and branch numbers. Notably, electrophysiology analyses showed defects in excitatory and inhibitory synaptic transmission. Furthermore, transcriptome analyses revealed that multiple biological pathways related to neuron projection, motility and regulation of neurogenesis were disrupted in cells with SHANK3 knockdown. In conclusion, utilizing a human iPSC-based neural induction model, this study presented combined morphological, electrophysiological and transcription evidence that support that SHANK3 as an intrinsic, cell autonomous factor that controls cellular function development in human neurons.https://www.frontiersin.org/article/10.3389/fnana.2019.00023/fullinduced pluripotent stem cellsneural stem cellsSHANK3electrophysiologyRNA-Seqautism |