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

• DOI: 10.1016/j.celrep.2017.03.047
• Publication Date: 2017-04-04T17:37:33Z
• Authors: Vira Iefremova; George Manikakis; Olivia Krefft; Ammar Jabali; Kevin Weynans; Ruven Wilkens; Fabio Marsoner; Björn Brändl; Franz-Josef Müller; Philipp Koch; Julia Ladewig
• Keywords: Organoid; Cell fate determination; Forebrain

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