Induction of Expansion and Folding in Human Cerebral Organoids

Publication date: Available online 29 December 2016
Source:Cell Stem Cell
Author(s): Yun Li, Julien Muffat, Attya Omer, Irene Bosch, Madeline A. Lancaster, Mriganka Sur, Lee Gehrke, Juergen A. Knoblich, Rudolf Jaenisch
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.

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Teaser

The growth and structural formation of the human cortex can be modeled in vitro using cerebral organoids. In this article, Li, Muffat, and colleagues show that enhancing the PTEN-AKT signaling pathway leads to the generation of human cerebral organoids that are expanded in size and display surface folding.


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