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Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination

Title
Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination
Author
Ramakrishna Suresh
Keywords
PRIMARY CILIA; AUTOPHAGOSOME FORMATION; REGULATES MULTIPOLAR; TUBEROUS SCLEROSIS; BIPOLAR TRANSITION; MIGRATING NEURONS; CEREBRAL-CORTEX; GENE; DYSPLASIA; MALFORMATIONS
Issue Date
2018-07
Publisher
CELL PRESS
Citation
NEURON, v. 99, no. 1, page. 83-97.e7
Abstract
Focal malformations of cortical development (FMCDs), including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in MTOR have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in MTOR, we discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. We found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, we found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in MTOR contribute to the pathogenesis of cortical dyslamination in FMCDs.
URI
https://www.cell.com/neuron/fulltext/S0896-6273(18)30437-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627318304379%3Fshowall%3Dtruehttps://repository.hanyang.ac.kr/handle/20.500.11754/119383
ISSN
0896-6273; 1097-4199
DOI
10.1016/j.neuron.2018.05.039
Appears in Collections:
GRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원) > ETC
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