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Cell Stem Cell. 2017 Mar 2;20(3):385-396.e3. doi: 10.1016/j.stem.2016.11.017. Epub 2016 Dec 29.

Induction of Expansion and Folding in Human Cerebral Organoids.

Author information

1
The Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
2
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
4
The Picower Institute for Learning and Memory, Cambridge, MA 02139, USA.
5
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA.
6
The Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA. Electronic address: jaenisch@wi.mit.edu.

Abstract

An expansion of the cerebral neocortex is thought to be the foundation for the unique intellectual abilities of humans. It has been suggested that an increase in the proliferative potential of neural progenitors (NPs) underlies the expansion of the cortex and its convoluted appearance. Here we show that increasing NP proliferation induces expansion and folding in an in vitro model of human corticogenesis. Deletion of PTEN stimulates proliferation and generates significantly larger and substantially folded cerebral organoids. This genetic modification allows sustained cell cycle re-entry, expansion of the progenitor population, and delayed neuronal differentiation, all key features of the developing human cortex. In contrast, Pten deletion in mouse organoids does not lead to folding. Finally, we utilized the expanded cerebral organoids to show that infection with Zika virus impairs cortical growth and folding. Our study provides new insights into the mechanisms regulating the structure and organization of the human cortex.

KEYWORDS:

AKT; Dengue; PTEN; Zika; cerebral organoids; cortical development; human embryonic stem cells; microcephaly; outer SVZ; outer radial glia

PMID:
28041895
PMCID:
PMC6461394
DOI:
10.1016/j.stem.2016.11.017
[Indexed for MEDLINE]
Free PMC Article

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