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

Guanqun Huang, Shuting Chen, Xiaoxia Chen, Jiajun Zheng, Zhuoran Xu, Abolfazl Doostparast Torshizi, Siyi Gong, Qingpei Chen, Xiaokuang Ma, Jiandong Yu, Libing Zhou, Shenfeng Qiu, Kai Wang, Lingling Shi

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number23
JournalFrontiers in Neuroanatomy
Volume13
DOIs
StatePublished - Feb 18 2019

Keywords

  • Autism
  • Electrophysiology
  • Induced pluripotent stem cells
  • Neural stem cells
  • RNA-Seq
  • SHANK3
  • Transcriptome

ASJC Scopus subject areas

  • Anatomy
  • Neuroscience (miscellaneous)
  • Cellular and Molecular Neuroscience

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    Huang, 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., & Shi, L. (2019). Uncovering the functional link between SHANK3 deletions and deficiency in neurodevelopment using iPSC-derived human neurons. Frontiers in Neuroanatomy, 13, [23]. https://doi.org/10.3389/fnana.2019.00023