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

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.

Copb2is essential for embryogenesis and hypomorphic mutations cause human microcephaly

“…A major difference between the patients discussed here and the mouse models we created was Additionally, we did find a reduction in layer V CTIP2-positive neurons in the COPB2 R254C/Zfn mice, which is a reported feature in mouse models of microcephaly (43). It is also worth noting that the probands themselves were significantly underweight in addition to being microcephalic (Fig 1).…”

A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature

“…observed in these animals (Chen et al 2014;Jayaraman et al 2016;Sgourdou et al 2017). Abnormalities in the centriole duplication, spindle pole orientation, and symmetric/ asymmetric division of neural progenitor cells and defects in the mitotic progression were noticed (Bogoyevitch et al 2012;Chen et al 2014;Jayaraman et al 2016;Sgourdou et al 2017). Premature delamination of progenitors from the germinal zones and increased apoptosis were also suggested in these experiments as the cause of reduced brain size (Bilgüvar et al 2010;Bogoyevitch et al 2012;Chen et al 2014;Farag et al 2013;Jayaraman et al 2016;Nicholas et al 2010;Sgourdou et al 2017;Yu et al 2010).…”

“…observed in these animals (Chen et al 2014;Jayaraman et al 2016;Sgourdou et al 2017). Abnormalities in the centriole duplication, spindle pole orientation, and symmetric/ asymmetric division of neural progenitor cells and defects in the mitotic progression were noticed (Bogoyevitch et al 2012;Chen et al 2014;Jayaraman et al 2016;Sgourdou et al 2017).…”

“…Studies by immunocytochemistry revealed that WDR62 protein showed cytosolic distribution in the interphase but it accumulated strongly at the spindle poles during mitosis (Bogoyevitch et al 2012;Farag et al 2013;Nicholas et al 2010;Sgourdou et al 2017;Yu et al 2010). Fibroblasts from patient with homozygous WDR62 mutation or cells transfected with missense and frameshift mutations in WDR62 failed to show protein expression at the spindle poles (Farag et al 2013;Nicholas et al 2010;Sgourdou et al 2017). WDR62 recruitment coincides with increased activity of Aurora A kinase, a centrosomal and spindle-associated protein that regulates spindle architecture and stability during mitosis (Carmena et al 2009).…”

“…While symmetrical division of a neuroprogenitor cell results in the generation of two identical neuroprogenitor cells (thereby increasing the progenitor pool), asymmetrical division leads to the production of one progenitor cell (thereby maintaining the progenitor pool) and a committed precursor, which eventually undergoes migration and differentiates into neuron (Barbelanne and Tsang 2014). In vivo experiments on mice with knockdown or genetic inactivation of Wdr62 and in vitro tests on cells with WDR62/ Wdr62 mutations led to significant progress in the understanding the pathogenesis of microcephaly in patients with WDR62 mutations (Bogoyevitch et al 2012;Chen et al 2014;Jayaraman et al 2016;Sgourdou et al 2017). Impaired proliferation of neural progenitors and reduced brain size were…”