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

Johannes Klaus; Sabina Kanton; Christina Kyrousi; Ane Cristina Ayo-Martin; Rossella Di Giaimo; Stephan Riesenberg; Adam C. O’Neill; J. Gray Camp; Chiara Tocco; Malgorzata Santel; Ejona Rusha; Micha Drukker; Mariana Schroeder; Magdalena Götz; Stephen P. Robertson; Barbara Treutlein; Silvia Cappello

doi:10.1038/s41591-019-0371-0

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

Johannes Klaus, Sabina Kanton, Christina Kyrousi, Ane Cristina Ayo-Martin, Rossella Di Giaimo, Stephan Riesenberg, Adam C. O’Neill, J. Gray Camp, Chiara Tocco, Malgorzata Santel, Ejona Rusha, Micha Drukker, Mariana Schroeder, Magdalena Götz, Stephen P. Robertson, Barbara Treutlein, Silvia Cappello

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

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 conditions². 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.

Original language	English
Pages (from-to)	561-568
Number of pages	8
Journal	Nature Medicine
Volume	25
Issue number	4
DOIs	https://doi.org/10.1038/s41591-019-0371-0
State	Published - 1 Apr 2019
Externally published	Yes

Bibliographical note

Funding Information:
We thank the families participating in this study for their involvement. We thank Y. Lu for help generating the microRNAs, M. Karow and I. Buchsbaum for helping with experiments and fruitful discussions in the lab, T. Öztürk for excellent technical support, A. Weigert for organoid culture, J. Kageyama for helping with data processing, R. Snabel for helping with Smart-seq2 libraries, the Core Unit Flow Cytometry at the Zentrum für Infektionsmedizin (veterinary faculty of the University of Leipzig) and the Core Unit Qualitätsmanagement/Technologieplattform at the Sächsischer Inkubator für Klinische Translation (SIKT) in Leipzig for karyotyping. This work was supported by funding from the DFG CA1205/2-1 (S.C.), ForIPS (M.G.), by the Max Planck Society (S.C., B.T.), by the Boehringer Ingelheim Fonds (S.K.), by the Health Research Council of NZ and Curekids (S.P.R.) and by an ERC Starting Grant (B.T.).

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Klaus, J., Kanton, S., Kyrousi, C., Ayo-Martin, A. C., Di Giaimo, R., Riesenberg, S., O’Neill, A. C., Camp, J. G., Tocco, C., Santel, M., Rusha, E., Drukker, M., Schroeder, M., Götz, M., Robertson, S. P., Treutlein, B., & Cappello, S. (2019). Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia. Nature Medicine, 25(4), 561-568. https://doi.org/10.1038/s41591-019-0371-0

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title = "Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia",

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 conditions2. 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) lines1,3. 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.",

author = "Johannes Klaus and Sabina Kanton and Christina Kyrousi and Ayo-Martin, {Ane Cristina} and {Di Giaimo}, Rossella and Stephan Riesenberg and O{\textquoteright}Neill, {Adam C.} and Camp, {J. Gray} and Chiara Tocco and Malgorzata Santel and Ejona Rusha and Micha Drukker and Mariana Schroeder and Magdalena G{\"o}tz and Robertson, {Stephen P.} and Barbara Treutlein and Silvia Cappello",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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doi = "10.1038/s41591-019-0371-0",

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Klaus, J, Kanton, S, Kyrousi, C, Ayo-Martin, AC, Di Giaimo, R, Riesenberg, S, O’Neill, AC, Camp, JG, Tocco, C, Santel, M, Rusha, E, Drukker, M, Schroeder, M, Götz, M, Robertson, SP, Treutlein, B & Cappello, S 2019, 'Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia', Nature Medicine, vol. 25, no. 4, pp. 561-568. https://doi.org/10.1038/s41591-019-0371-0

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T1 - Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia

AU - Klaus, Johannes

AU - Kanton, Sabina

AU - Kyrousi, Christina

AU - Ayo-Martin, Ane Cristina

AU - Di Giaimo, Rossella

AU - Riesenberg, Stephan

AU - O’Neill, Adam C.

AU - Camp, J. Gray

AU - Tocco, Chiara

AU - Santel, Malgorzata

AU - Rusha, Ejona

AU - Drukker, Micha

AU - Schroeder, Mariana

AU - Götz, Magdalena

AU - Robertson, Stephen P.

AU - Treutlein, Barbara

AU - Cappello, Silvia

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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 conditions2. 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) lines1,3. 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.

AB - 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 conditions2. 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) lines1,3. 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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Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia

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