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.
Highlights
Malformations of cerebral cortical development (MCD) are the outcome of disruptions in the precisely orchestrated series of events that occur during embryonic and early postnatal life and define the specification of neuronal identity and, the execution of neuronal differentiation and connectivity both within and outside the cerebral cortex
We examine the effects of WDR62 disruption on neocortical development using a newly generated mouse model, identify a novel homozygous mutation in WDR62 in two affected siblings with microcephaly and severe brain malformations, and characterize its functional impact using patient-derived fibroblasts
We establish a critical role of WDR62 in proliferation of late neocortical progenitor cells and brain size and show that its disruption causes abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation
Summary
Malformations of cerebral cortical development (MCD) are the outcome of disruptions in the precisely orchestrated series of events that occur during embryonic and early postnatal life and define the specification of neuronal identity and, the execution of neuronal differentiation and connectivity both within and outside the cerebral cortex. MCPH2 (OMIM 604317), the second most common form of primary microcephaly, is caused by recessive mutations in WDR6215–17, a gene encoding a WD repeat-containing protein. Members of this large pan-eukaryotic protein family are thought to serve as rigid www.nature.com/scientificreports/. Our findings provide novel mechanistic insight into WDR62 function in cortical development, demonstrating a complex effect on the cell cycle of neocortical progenitors, and may help explain the large spectrum of cortical malformations associated with WDR62 mutations causing microcephaly
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