Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors
Autor: | Jana Schroth, William B. Dobyns, Hülya Kayserili, Jean-Baptiste Rivière, Haig Keshishian, Murat Gunel, Katsuhito Yasuno, Neil C. Chi, Shrikant Mane, Duygu Dölen, Burçin Baran, Richard P. Lifton, Caner Çağlar, Ahmet Okay Caglayan, Heba A.A. Hossni, Hüseyin Per, Ashleigh E. Schaffer, E. Zeynep Erson-Omay, Octavian Henegariu, Sefer Kumandaş, Cengiz Dilber, Fernando Vonhoff, Chiswili Chabu, Jacob F Baranoski, Wenqi Han, Kaya Bilguvar, Tian Xu, Gozde Tugce Akgumus, Rasim Ozgur Rosti, Hakan Gümüş, Shu Tu, Ketu Mishra-Gorur, Sayoko Nishimura, Emily Spencer, Nenad Sestan, Frank J. Minja, Joseph G. Gleeson, Maha S. Zaki, Çağri Çağlar, Angeliki Louvi |
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Přispěvatelé: | ÇAĞLAR, CANER |
Rok vydání: | 2014 |
Předmět: |
Microtubule-associated protein
Neurogenesis Neuroscience(all) Cell Count Katanin Spindle Apparatus Biology medicine.disease_cause Article Mice 03 medical and health sciences 0302 clinical medicine Neural Stem Cells Neuroblast medicine Animals Drosophila Proteins Humans Progenitor cell Zebrafish Mitosis Adenosine Triphosphatases Mutation General Neuroscience Optic Lobe Nonmammalian Brain Dendrites biology.organism_classification Spindle apparatus medicine.anatomical_structure Centrosome 030220 oncology & carcinogenesis Cerebral malformations Microcephaly biology.protein Drosophila Neuron Microtubule-Associated Proteins Neuroscience Cell Division 030217 neurology & neurosurgery |
Popis: | SummaryExome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development. |
Databáze: | OpenAIRE |
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