Format

Send to

Choose Destination
Mol Psychiatry. 2018 Mar;23(3):735-746. doi: 10.1038/mp.2017.185. Epub 2017 Sep 26.

Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development.

Author information

1
Cells & Behavior Unit, Department of Basic and Clinical Neuroscience, Institute of Psychiatry Psychology & Neuroscience, King's College London, London, UK.
2
CNS Discovery/F-Hoffmann-La Roche Ltd, Basel, Switzerland.
3
Department of Cellular and Molecular Medicine School of Medicine University of California, San Diego, CA, USA.
4
Developmental Neurobiology/New Hunt's House Guy's Campus, King's College London, London, UK.
5
MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.
6
School of Biological Sciences, Royal Holloway, University of London, Egham, UK.
7
Division of Advanced Therapies, National Institute for Biological Standards and Control, Hertfordshire, UK.

Abstract

Shank3 is a structural protein found predominantly at the postsynaptic density. Mutations in the SHANK3 gene have been associated with risk for autism spectrum disorder (ASD). We generated induced pluripotent stem cells (iPSCs) from control individuals and from human donors with ASD carrying microdeletions of SHANK3. In addition, we used Zinc finger nucleases to generate isogenic SHANK3 knockout human embryonic stem (ES) cell lines. We differentiated pluripotent cells into either cortical or olfactory placodal neurons. We show that patient-derived placodal neurons make fewer synapses than control cells. Moreover, patient-derived cells display a developmental phenotype: young postmitotic neurons have smaller cell bodies, more extensively branched neurites, and reduced motility compared with controls. These phenotypes were mimicked by SHANK3-edited ES cells and rescued by transduction with a Shank3 expression construct. This developmental phenotype is not observed in the same iPSC lines differentiated into cortical neurons. Therefore, we suggest that SHANK3 has a critical role in neuronal morphogenesis in placodal neurons and that early defects are associated with ASD-associated mutations.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center