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.
Pubmed ID: 29937275 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This polyclonal targets p62 / SQSTM1
View all literature mentionsThis monoclonal targets BrdU
View all literature mentionsThis polyclonal targets Histone H3 (phospho S10) antibody - Mitosis Marker
View all literature mentionsThis monoclonal targets DYKDDDDK Tag (9A3) Mouse mAb (Binds to same epitope as Sigma's FLAG M2 )
View all literature mentionsThis monoclonal targets c-Myc
View all literature mentionsThis monoclonal targets alpha-Tubulin antibody produced in mouse
View all literature mentionsThis monoclonal targets S6 Ribosomal Protein
View all literature mentionsThis polyclonal targets ADCY3
View all literature mentionsThis polyclonal targets Human Ctip2
View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser240/244) (D68F8) XP Rabbit mAb
View all literature mentionsThis polyclonal targets Ki67 antibody - Proliferation Marker
View all literature mentionsThis monoclonal targets Tubulin, gamma
View all literature mentionsThis monoclonal targets Polyglutamylation Modification
View all literature mentionsThis monoclonal targets derived from the hybridoma 6-11B-1 produced by the fusion of mouse myeloma cells and splenocytes from a mouse immunized with acetylated tubulin from the outer arm of Strongylocentrotus purpuratus (sea urchin).
View all literature mentionsThis polyclonal targets ARL13B
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NIH 3T3 is a Spontaneously immortalized cell line with a species of origin Mus musculus
View all literature mentionsThis polyclonal targets p62 / SQSTM1
View all literature mentions