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Cell Rep. 2017 Apr 4;19(1):50-59. doi: 10.1016/j.celrep.2017.03.047.

An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome.

Author information

1
Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
2
Department of Psychiatry and Psychotherapy, University Hospital Schleswig Holstein, Kiel 24105, Germany.
3
Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany. Electronic address: philipp.koch@uni-bonn.de.
4
Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany. Electronic address: jladewig@uni-bonn.de.

Abstract

Miller-Dieker syndrome (MDS) is caused by a heterozygous deletion of chromosome 17p13.3 involving the genes LIS1 and YWHAE (coding for 14.3.3ε) and leads to malformations during cortical development. Here, we used patient-specific forebrain-type organoids to investigate pathological changes associated with MDS. Patient-derived organoids are significantly reduced in size, a change accompanied by a switch from symmetric to asymmetric cell division of ventricular zone radial glia cells (vRGCs). Alterations in microtubule network organization in vRGCs and a disruption of cortical niche architecture, including altered expression of cell adhesion molecules, are also observed. These phenotypic changes lead to a non-cell-autonomous disturbance of the N-cadherin/β-catenin signaling axis. Reinstalling active β-catenin signaling rescues division modes and ameliorates growth defects. Our data define the role of LIS1 and 14.3.3ε in maintaining the cortical niche and highlight the utility of organoid-based systems for modeling complex cell-cell interactions in vitro.

KEYWORDS:

Lissencephaly; Miller-Dieker-Syndrome; brain organoids; disease modeling; induced pluripotent stem cells; neurodevelopmental disorders; ventricular zone niche signaling

PMID:
28380362
DOI:
10.1016/j.celrep.2017.03.047
[Indexed for MEDLINE]
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