title: Induction of Expansion and Folding in Human Cerebral Organoids.
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.
authors.affiliation: The Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Muffat
authors.affiliation: The Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Attya
authors.initials: A
authors.lastname: Omer
authors.affiliation: Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Bosch
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Madeline A
authors.initials: MA
authors.lastname: Lancaster
authors.affiliation: The Picower Institute for Learning and Memory, Cambridge, MA 02139, USA.
authors.forename: Mriganka
authors.initials: M
authors.lastname: Sur
authors.affiliation: 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.
authors.forename: Lee
authors.initials: L
authors.lastname: Gehrke
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Juergen A
authors.initials: JA
authors.lastname: Knoblich
authors.affiliation: 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.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054022:Cerebrum / Q000166:cytology*; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009940:Organoids / Q000166:cytology* / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000071244:Zika Virus / Q000187:drug effects / Q000502:physiology; D000071243:Zika Virus Infection / Q000473:pathology / Q000821:virology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase
keywords: AKT; Dengue; PTEN; Zika; cerebral organoids; cortical development; human embryonic stem cells; microcephaly; outer SVZ; outer radial glia