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

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. [Display omitted] •Homogeneous forebrain-type organoids reflect early cortical development in vitro•MDS-derived organoids show reduced expansion rate caused by premature neurogenesis•MDS-derived organoids exhibit alterations in cortical niche architecture•Niche disruption leads to a non-cell-autonomous disturbance of β-catenin signaling Using Miller-Dieker-syndrome-specific iPSC-derived forebrain-type organoid cultures, Iefremova et al. find that a disturbance of cortical niche signaling leads to alterations in N-cadherin/β-catenin signaling that result in a non-cell-autonomous expansion defect of ventricular zone radial glia cells.