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  Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia

Klaus, J., Kanton, S., Kyrousi, C., Ayo-Martin, A. C., Di Giaimo, R., Riesenberg, S., et al. (2019). Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia. Nature Medicine, 25(4), 561-+. doi:10.1038/s41591-019-0371-0.

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 Creators:
Klaus, Johannes1, Author           
Kanton, Sabina2, 3, Author           
Kyrousi, Christina1, Author           
Ayo-Martin, Ane Cristina4, Author
Di Giaimo, Rossella4, Author           
Riesenberg, Stephan3, 5, 6, Author           
O'Neill, Adam C., Author
Camp, J. Gray5, 6, 7, Author           
Tocco, Chiara, Author
Santel, Malgorzata2, 5, Author           
Rusha, Ejona, Author
Drukker, Micha, Author
Schroeder, Mariana8, Author           
Goetz, Magdalena9, Author           
Robertson, Stephen P., Author
Treutlein, Barbara10, Author           
Cappello, Silvia1, Author           
Affiliations:
1Max Planck Research Group Developmental Neurobiology (Silvia Cappello), Max Planck Institute of Psychiatry, Max Planck Society, ou_2173645              
2Single Cell Genomics, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Max Planck Society, ou_2173644              
3The Leipzig School of Human Origins (IMPRS), Max Planck Institute for Evolutionary Anthropology, Max Planck Society, ou_1497688              
4Max Planck Institute of Psychiatry, Max Planck Society, ou_1607137              
5Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Max Planck Society, ou_1497672              
6Neandertals and more, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Max Planck Society, ou_2074328              
7Modern and Archaic Human Cell Biology, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Max Planck Society, ou_2477693              
8Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035294              
9Research Group: Neuronal Specificity / Götz, MPI of Neurobiology, Max Planck Society, ou_1113562              
10Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society, ou_2340692              

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 Abstract: Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions(2). Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines(1,3). Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH.

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Language(s): eng - English
 Dates: 2019-03-11
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000463342800016
DOI: 10.1038/s41591-019-0371-0
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Title: Nature Medicine
  Other : Nat. Med.
Source Genre: Journal
 Creator(s):
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Publ. Info: New York, NY : Nature Pub. Co.
Pages: - Volume / Issue: 25 (4) Sequence Number: - Start / End Page: 561 - + Identifier: ISSN: 1078-8956
CoNE: https://pure.mpg.de/cone/journals/resource/954925606824