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.