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  Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

Rosebrock, D., Arora, S., Mutukula, N., Volkman, R., Gralinska, E., Balaskas, A., et al. (2022). Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells. Nature Cell Biology, 24, 981-995. doi:10.1038/s41556-022-00929-5.

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NatCellBiol_Rosebrock et al_2022.pdf (Publisher version), 21MB
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 Creators:
Rosebrock, Daniel1, Author           
Arora, Sneha2, Author           
Mutukula, Naresh2, Author           
Volkman, Rotem, Author
Gralinska, Elzbieta1, Author           
Balaskas, Anastasios3, Author           
Aragonés Hernández, Amèlia2, Author           
Buschow, Rene4, Author           
Brändl, Björn3, Author           
Müller, Franz-Josef5, Author           
Arndt, Peter F.6, Author           
Vingron, Martin1, Author           
Elkabetz, Yechiel2, Author           
Affiliations:
1Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
2Human Brain & Neural Stem Cell Studies (Yechiel Elkabetz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014186              
3Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
4Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
5Cellular Phenotyping (Franz-Josef Müller), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014190              
6Evolutionary Genomics (Peter Arndt), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479638              

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 Abstract: Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early Dual SMAD and WNT inhibition course is necessary and sufficient to establish robust and lasting cortical organoid NSC identity, efficiently suppressing non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC-specification capacity. Accordingly, this method selectively enriches for outer radial glia NSCs, which cyto-architecturally demarcate well-defined outer sub-ventricular-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD and WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring of fundamental molecular and cyto-architectural features of cortical development and meaningful disease modelling.

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Language(s): eng - English
 Dates: 2022-04-282022-06-28
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/s41556-022-00929-5
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Title: Nature Cell Biology
  Other : 'Nat. Cell Biol.'
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: 15 Volume / Issue: 24 Sequence Number: - Start / End Page: 981 - 995 Identifier: ISSN: 1465-7392
CoNE: https://pure.mpg.de/cone/journals/resource/954925625310