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Sci Rep. 2017 Mar 8;7:43708. doi: 10.1038/srep43708.

Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly.

Author information

1
Departments of Neurosurgery and Neuroscience, Program on Neurogenetics, Yale School of Medicine, New Haven, CT, 06520, USA.
2
Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.
3
Departments of Neuroscience, Genetics and Psychiatry, Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, 06520, USA.
4
Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul, Turkey.
5
Department of Genetics, Yale School of Medicine, New Haven, CT, 06520, USA.

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.

PMID:
28272472
PMCID:
PMC5341122
DOI:
10.1038/srep43708
[Indexed for MEDLINE]
Free PMC Article

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