Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia
Abstract
Classical lissencephaly is a genetic neurological disorder associated with mental retardation and intractable epilepsy, and Miller-Dieker syndrome (MDS) is the most severe form of the disease. In this study, to investigate the effects of MDS on human progenitor subtypes that control neuronal output and influence brain topology, we analyzed cerebral organoids derived from control and MDS-induced pluripotent stem cells (iPSCs) using time-lapse imaging, immunostaining, and single-cell RNA sequencing. We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion and severe apoptosis of the founder neuroepithelial stem cells, accompanied by increased horizontal cell divisions. We also identified a mitotic defect in outer radial glia, a progenitor subtype that is largely absent from lissencephalic rodents but critical for human neocortical expansion. Our study, therefore, deepens our understanding of MDS cellular pathogenesis and highlights the broad utility of cerebral organoids for modeling human neurodevelopmental disorders.
Additional Information
© 2016 Elsevier Inc. Received 8 July 2016; revised 16 October 2016; accepted 16 December 2016; available online 19 January 2017; published January 19, 2017. The authors are grateful to Joseph Loturco, Catherine Priest, Haim Belinson, Carmen Sandoval Espinosa, and members of the A.R.K. and A.W.B. labs for helpful feedback on the manuscript. We thank Melanie Bedolli, Lillian Adame, and Yinging Wang for technical support. M.B. was supported by a postdoctoral fellowship from the California Institute for Regenerative Medicine, CIRM (Grant TG2-01153), and a K99 career development award from the National Institute for Neurological Disorders and Stroke (Grant 5K99NS088572). This research was funded by NIH Grants NS075998 and MH105989 and CIRM Award GCIR-06673 (to A.R.K.).Attached Files
Accepted Version - nihms842447.pdf
Supplemental Material - mmc1.pdf
Supplemental Material - mmc2.xlsx
Supplemental Material - mmc3.mp4
Supplemental Material - mmc4.mp4
Supplemental Material - mmc5.mp4
Supplemental Material - mmc6.mp4
Supplemental Material - mmc7.mp4
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Additional details
- PMCID
- PMC5667944
- Eprint ID
- 73813
- Resolver ID
- CaltechAUTHORS:20170130-100155734
- TG2-01153
- California Institute for Regenerative Medicine (CIRM)
- 5K99NS088572
- NIH
- NS075998
- NIH
- MH105989
- NIH
- GCIR-06673
- California Institute for Regenerative Medicine (CIRM)
- Created
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2017-01-30Created from EPrint's datestamp field
- Updated
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2021-11-11Created from EPrint's last_modified field