Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons

Frontiers in Neuroanatomy

Kai Wang¹  Abolfazl Doostparast Torshizi¹  Lingling Shi²  Guanqun Huang³  Shenfeng Qiu³  Xiaokuang Ma³  Zhuoran Xu⁴  Libing Zhou⁵  Qingpei Chen⁵  Jiandong Yu⁵  Siyi Gong⁵  Jiajun Zheng⁵  Shuting Chen⁵  Xiaoxia Chen⁵ 

[1] Children’s Hospital of Philadelphia, Philadelphia, PA, United States;Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China;Department of Basic Medical Sciences, College of Medicine – Phoenix, The University of Arizona, Phoenix, AZ, United States;Department of Biomedical Informatics, Columbia University, New York, NY, United States;Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, China;

关键词: induced pluripotent stem cells;    neural stem cells;    SHANK3;    electrophysiology;    RNA-Seq;    autism;   

DOI  :  10.3389/fnana.2019.00023

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown