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

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.

Genetics and mechanisms leading to human cortical malformations

“…A switch from symmetric to asymmetric cell division of apical RGCs was observed, as well as alterations of the N-Cadherin/β-Catenin signaling pathway, showing that a reduction of Wnt activity leads to premature neurogenesis. These alterations in MDS-derived organoids were rescued by Wnt activation [299]. Thus, these studies highlight the potential of organotypic cell-culture models to contribute to the understanding of developmental mechanisms underlying MCDs.…”

“…It was also shown that MDS bRG cells remained in mitosis for prolonged periods prior to cytokinesis and thus, authors suggest the possible involvement of bRG cell dysfunction in the pathogenesis of human LIS [298]. A second study has also used patient-specific forebrain-type organoids to study MDS pathology [299]. Premature neurogenesis was found to reduce the expansion of MDS patient-specific organoids, characterized with a panel of parameters.…”

The use of brain organoids to investigate neural development and disease

“…The organoids also displayed severe apoptosis of neuroepithelial stem cells in the ventricular-like zone and a mitotic defect in oRGs 50 . A second report also observed changes in the division mode of radial glial cells in MDS organoids and identified non-cell-autonomous defects in WNT signalling as an underlying mechanism 67 .…”

“…However, they can also be used to discover human-specific phenotypes, providing an advantage over existing mouse models. Two recent papers used brain organoids to investigate the cellular basis of Miller–Dieker syndrome (MDS), a severe congenital form of lissencephaly 50,67 . Classically, lissencephaly has been studied in mouse models, which have the obvious disadvantage of being naturally lissencephalic.…”

Translational potential of human brain organoids

“…Their results identified several cellular features of this classical form of lissencephaly, including aberrant cell cycle of outer radial glia and non–cell‐autonomous alteration of WNT signaling 42, 43…”