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Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly.
- Source :
-
Scientific reports [Sci Rep] 2017 Mar 08; Vol. 7, pp. 43708. Date of Electronic Publication: 2017 Mar 08. - Publication Year :
- 2017
-
Abstract
- Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase. Expression of WDR62 is closely correlated with components of the chromosome passenger complex (CPC), a key regulator of mitosis. Wild type WDR62, but not disease-associated mutant forms, interacts with the CPC core enzyme Aurora kinase B and staining of CPC components at centromeres is altered in patient-derived fibroblasts. Our findings demonstrate critical and diverse functions of WDR62 in neocortical development and provide insight into the mechanisms by which its disruption leads to a plethora of structural abnormalities.
- Subjects :
- Animals
Brain abnormalities
Brain metabolism
Brain pathology
Cell Cycle genetics
Cell Cycle Proteins
Cell Differentiation genetics
Cell Proliferation
Consanguinity
Disease Models, Animal
Fluorescent Antibody Technique
Gene Expression
Humans
Male
Mice
Mice, Knockout
Microcephaly diagnostic imaging
Microcephaly pathology
Mutation
Neural Stem Cells metabolism
Pedigree
Whole Genome Sequencing
Aurora Kinase B genetics
Centrosome metabolism
Epistasis, Genetic
Inheritance Patterns
Microcephaly genetics
Nerve Tissue Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 7
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 28272472
- Full Text :
- https://doi.org/10.1038/srep43708