Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons
Doostparast Torshizi, Abolfazl
AffiliationUniv Arizona, Dept Basic Med Sci, Coll Med Phoenix
induced pluripotent stem cells
neural stem cells
MetadataShow full item record
PublisherFRONTIERS MEDIA SA
CitationHuang G, Chen S, Chen X, Zheng J, Xu Z, Doostparast Torshizi A, Gong S, Chen Q, Ma X, Yu J, Zhou L, Qiu S, Wang K and Shi L (2019) Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons. Front. Neuroanat. 13:23. doi: 10.3389/fnana.2019.00023
JournalFRONTIERS IN NEUROANATOMY
Rights© 2019 Huang, Chen, Chen, Zheng, Xu, Doostparast Torshizi, Gong, Chen, Ma, Yu, Zhou, Qiu, Wang and Shi. 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.
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AbstractSHANK3 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.
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VersionFinal published version
SponsorsNational Natural Science Foundation of China ; National Key Research and Development Program of China, Stem Cell and Translational Research [2017YFA0105102]; Guangzhou Science and Technology Innovation Development special fund project ; Fundamental Research Funds for the Central Universities of China ; Program of Introducing Talents of Discipline to Universities [B14036]
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