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Front. Neuroanat. | doi: 10.3389/fnana.2019.00023

Uncovering the functional link between SHANK3 deletions and deficiency in neurodevelopment using iPSC-derived human neurons

 Lingling Shi1*, Guanqun Huang1, Xiaoxia Chen1,  Jiajun Zheng1, Zhuoran Xu2,  Abolfazl D. Torshizi2, 3, Siyi Gong1, Sai Kang1, Xiaokuang Ma4, Jiandong Yu1,  Libing Zhou1, Shenfeng Qiu4 and  Kai Wang2, 3
  • 1Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, China
  • 2Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, United States
  • 3Children's Hospital of Philadelphia, United States
  • 4University of Arizona College of Medicine-Phoenix, Department of Basic Medical Sciences, College of Medicine Phoenix,University of Arizona, United States

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 multiplebiological 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.

Keywords: Induced Pluripotent Stem Cells, Neural Stem Cells, Shank3, Electrophysiology, RNA-Seq, autism, tran

Received: 01 Jun 2018; Accepted: 07 Feb 2019.

Edited by:

Basilis Zikopoulos, Boston University, United States

Reviewed by:

Chiara Verpelli, Institute of Neuroscience (IN), Italy
Thomas Bourgeron, Institut Pasteur, France  

Copyright: © 2019 Shi, Huang, Chen, Zheng, Xu, Torshizi, Gong, Kang, Ma, Yu, Zhou, Qiu and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Lingling Shi, Jinan University, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Guangzhou, 510632, China, tlingshi@jnu.edu.cn