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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), 561-568. doi:10.1038/s41591-019-0371-0.

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Klaus, Johannes1, Author           
Kanton, Sabina, Author
Kyrousi, Christina1, Author           
Ayo-Martin, Ane Cristina1, 2, Author           
Di Giaimo, Rossella1, Author           
Riesenberg, Stephan, Author
O'Neill, Adam C., Author
Camp, J. Gray, Author
Tocco, Chiara1, Author           
Santel, Malgorzata, Author
Rusha, Ejona, Author
Drukker, Micha, Author
Schroeder, Mariana, Author
Goetz, Magdalena, Author
Robertson, Stephen P., Author
Treutlein, Barbara, Author
Cappello, Silvia, Author
Affiliations:
1Max Planck Research Group Developmental Neurobiology (Silvia Cappello), Max Planck Institute of Psychiatry, Max Planck Society, ou_2173645              
2IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_3318616              

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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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 Dates: 2019-03-11
 Publication Status: Published in print
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 Identifiers: ISI: 000463342800016
DOI: 10.1038/s41591-019-0371-0
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Title: NATURE MEDICINE
Source Genre: Journal
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Pages: - Volume / Issue: 25 (4) Sequence Number: - Start / End Page: 561 - 568 Identifier: ISSN: 1078-8956