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Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia

Bershteyn, Marina and Nowakowski, Tomasz J. and Pollen, Alex A. and Di Lullo, Elizabeth and Nene, Aishwarya and Wynshaw-Boris, Anthony and Kriegstein, Arnold R. (2017) Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia. Cell Stem Cell, 20 (4). pp. 435-449. ISSN 1934-5909. https://resolver.caltech.edu/CaltechAUTHORS:20170130-100155734

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[img] MS Excel (Table S1. Metadata for All Cells Used in Single-Cell Gene Expression Analysis, Related to Figure 5.) - Supplemental Material
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[img] Video (QuickTime) (Movie S1. Live Imaging Example of Vertical Division in the VZ-like Region of a Week 5 Organoid, Related to Figure 2.) - Supplemental Material
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[img] Video (QuickTime) (Movie S2. Live Imaging Example of Horizontal Division in the VZ-like Region of a Week 5 MDS Organoid, Related to Figure 2.) - Supplemental Material
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[img] Video (QuickTime) (Movie S3. Live Imaging Example of a WT Neuron Migrating on a Process Emanating from a Week 5 WT Organoid, Related to Figure 3.) - Supplemental Material
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[img] Video (QuickTime) (Movie S4. Live Imaging Examples of MDS Neurons Migrating on Processes Emanating from Week 5 MDS Organoids, Related to Figure 3.) - Supplemental Material
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[img] Video (QuickTime) (Movie S5. Live Imaging Examples of WT and MDS oRG-like Cell Divisions in Week 10 Organoids, Related to Figure 6.) - Supplemental Material
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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://doi.org/10.1016/j.stem.2016.12.007DOIArticle
http://www.sciencedirect.com/science/article/pii/S1934590916304635PublisherArticle
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.).
Funders:
Funding AgencyGrant Number
California Institute for Regenerative Medicine (CIRM)TG2-01153
NIH5K99NS088572
NIHNS075998
NIHMH105989
California Institute for Regenerative Medicine (CIRM)GCIR-06673
Subject Keywords:Human Lissencephaly; Cerebral Organoids; Outer Radial Glia; Migration; Spindle Orientation
Issue or Number:4
Record Number:CaltechAUTHORS:20170130-100155734
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170130-100155734
Official Citation:Marina Bershteyn, Tomasz J. Nowakowski, Alex A. Pollen, Elizabeth Di Lullo, Aishwarya Nene, Anthony Wynshaw-Boris, Arnold R. Kriegstein, Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia, Cell Stem Cell, Volume 20, Issue 4, 6 April 2017, Pages 435-449.e4, ISSN 1934-5909, http://doi.org/10.1016/j.stem.2016.12.007. (http://www.sciencedirect.com/science/article/pii/S1934590916304635)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73813
Collection:CaltechAUTHORS
Deposited By: Melissa Ray
Deposited On:30 Jan 2017 19:53
Last Modified:03 Oct 2019 16:31

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