NONO Regulates Cortical Neuronal Migration and Postnatal Neuronal Maturation.
Ontology highlight
ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC6864022 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
Publications
NONO Regulates Cortical Neuronal Migration and Postnatal Neuronal Maturation.
Liu Xiaoqing X Zheng Jiangli J Qi Shaojun S Shen Qin Q
Neuroscience bulletin 20190909 6
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Project description:During embryonic development, excitatory projection neurons migrate in the cerebral cortex giving rise to organised layers. Periventricular heterotopia (PH) is a group of aetiologically heterogeneous disorders in which a subpopulation of newborn projection neurons fails to initiate their radial migration to the cortex, ultimately resulting in bands or nodules of grey matter lining the lateral ventricles. Although a number of genes have been implicated in its cause, currently they only satisfactorily explain the pathogenesis of the condition for 50% of patients. Novel gene discovery is complicated by the extreme genetic heterogeneity recently described to underlie its cause. Here, we study the neurodevelopmental role of endothelin-converting enzyme-2 (ECE2) for which two biallelic variants have been identified in two separate patients with PH. Our results show that manipulation of ECE2 levels in human cerebral organoids and in the developing mouse cortex leads to ectopic localisation of neural progenitors and neurons. We uncover the role of ECE2 in neurogenesis, and mechanistically, we identify its involvement in the generation and secretion of extracellular matrix proteins in addition to cytoskeleton and adhesion.
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Project description:During embryonic development, the cerebral cortex is equipped with excitatory projection and inhibitory interneurons that migrate in organized layers. Periventricular heterotopia (PH) is a rare and heterogeneous disorder in which a subpopulation of new-born projection neurons fails to initiate their radial migration to the cortex, ultimately resulting in bands or nodules of grey matter lining the lateral ventricles underneath a normal cortex. For many years, few genes had been identified that cause this disorder upon disruption, but recently it was shown that PH is genetically a very heterogeneous disease. Here, we study the neurodevelopmental role of endothelin converting enzyme 2 (ECE2), biallelic mutations in which have been identified in two patients with PH. Our results show that manipulation of ECE2 levels or activity in human cerebral organoids and in the developing mouse cortex leads to ectopic localization of neural progenitors and neurons. We uncover the role of ECE2 in neurogenesis and, mechanistically, we identify its involvement in generation and secretion of extracellular matrix and in protein phosphorylation. This strongly suggests ECE2 as a novel candidate gene for PH.
2020-03-09 | PXD015571 | Pride
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