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

Cell Reports

Björn Brändl¹  Franz-Josef Müller¹  George Manikakis²  Fabio Marsoner²  Olivia Krefft²  Ammar Jabali²  Kevin Weynans²  Julia Ladewig²  Vira Iefremova²  Ruven Wilkens²  Philipp Koch² 

[1] Department of Psychiatry and Psychotherapy, University Hospital Schleswig Holstein, Kiel 24105, Germany;Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany;

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

DOI  :  10.1016/j.celrep.2017.03.047

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown