title: 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.
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
authors.forename: Vira
authors.initials: V
authors.lastname: Iefremova
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
authors.forename: George
authors.initials: G
authors.lastname: Manikakis
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Krefft
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
authors.forename: Ammar
authors.initials: A
authors.lastname: Jabali
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
authors.forename: Kevin
authors.initials: K
authors.lastname: Weynans
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
authors.forename: Ruven
authors.initials: R
authors.lastname: Wilkens
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marsoner
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Schleswig Holstein, Kiel 24105, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Brändl
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Schleswig Holstein, Kiel 24105, Germany.
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Müller
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany. Electronic address: philipp.koch@uni-bonn.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Koch
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany. Electronic address: jladewig@uni-bonn.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Ladewig
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism; D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D002455:Cell Division; D002540:Cerebral Cortex / Q000002:abnormalities / Q000473:pathology*; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000378:metabolism*; D063928:Ependymoglial Cells / Q000378:metabolism; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009940:Organoids / Q000378:metabolism*; D055153:Stem Cell Niche; D023822:Tissue Engineering; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D015820:Cadherins; D008869:Microtubule-Associated Proteins; C482983:YWHAE protein, human; D051176:beta Catenin; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human
keywords: Lissencephaly; Miller-Dieker-Syndrome; brain organoids; disease modeling; induced pluripotent stem cells; neurodevelopmental disorders; ventricular zone niche signaling