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Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons
- Source :
- Frontiers in Neuroanatomy, Vol 13 (2019)
- Publication Year :
- 2019
- Publisher :
- Frontiers Media S.A., 2019.
-
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.
Details
- Language :
- English
- ISSN :
- 16625129
- Volume :
- 13
- Database :
- Directory of Open Access Journals
- Journal :
- Frontiers in Neuroanatomy
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.0d3c36eb624333894f1743b9b65e42
- Document Type :
- article
- Full Text :
- https://doi.org/10.3389/fnana.2019.00023