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Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia
- Source :
- Nature Medicine, 25, Nature Medicine
- Publication Year :
- 2019
-
Abstract
- Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions(2). Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines(1,3). Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH.
- Subjects :
- Organoid
0301 basic medicine
Biology
Time-Lapse Imaging
General Biochemistry, Genetics and Molecular Biology
Cell Line
03 medical and health sciences
0302 clinical medicine
Periventricular Nodular Heterotopia
Cell Movement
Progenitor cell
Induced pluripotent stem cell
Cerebrum
Tumor Suppressor Protein
DCHS1
Sequence Analysis, RNA
Cadherin
Infant, Newborn
General Medicine
Neuron
Phenotype
Neural stem cell
3. Good health
Cell biology
Single-Cell Analysi
030104 developmental biology
030220 oncology & carcinogenesis
Mutation
Axon guidance
Human
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Nature Medicine, 25, Nature Medicine
- Accession number :
- edsair.doi.dedup.....2e13544b3b6e8d5f033c45744e8bf4cf