Loss of CDK5RAP2 affects neural but not non-neural mESC differentiation into cardiomyocytes

Abstract

Biallelic mutations in the gene encoding centrosomal CDK5RAP2 lead to autosomal recessive primary microcephaly (MCPH), a disorder characterized by pronounced reduction in volume of otherwise architectonical normal brains and intellectual deficit. The current model for the microcephaly phenotype in MCPH invokes a premature shift from symmetric to asymmetric neural progenitor-cell divisions with a subsequent depletion of the progenitor pool. The isolated neural phenotype, despite the ubiquitous expression of CDK5RAP2, and reports of progressive microcephaly in individual MCPH cases prompted us to investigate neural and non-neural differentiation of Cdk5rap2-depleted and control murine embryonic stem cells (mESC). We demonstrate an accumulating proliferation defect of neurally differentiating Cdk5rap2-depleted mESC and cell death of proliferative and early postmitotic cells. A similar effect does not occur in non-neural differentiation into beating cardiomyocytes, which is in line with the lack of non-central nervous system features in MCPH patients. Our data suggest that MCPH is not only caused by premature differentiation of progenitors, but also by reduced propagation and survival of neural progenitors.

Whole-exome sequencing identifies homozygous mutation in TTI2 in a child with primary microcephaly: a case report

“…It is not clear how deficits in PIKK proteins can cause neurodevelopmental defect. However, studies in animal models of MCPH have revealed important role of DNA damage response in embryonic neurogenesis [19][20][21]. By example, premature neurogenesis leading to a reduction in the number of neuronal cells was caused by a ventricular neural stem cell defect in MCPH models [22][23][24].…”

Autosomal Recessive Primary Microcephaly (MCPH): An Update

“…27,30,31 However, the latter is not the only underlying mechanism since some MCPH mouse models-where the cleavage plane is unaffected-still display microcephaly. 30,31 Additional studies in MCPH models have also identified defects in chromosome condensation, microtubule dynamics, cell cycle checkpoint control, and/or DNA damage-response signaling during embryonic neurogenesis 32,33 (►Fig. 3).…”

CDK5RAP2 Is Required to Maintain the Germ Cell Pool during Embryonic Development

“…Recent data link the brain phenotype to a stem cell defect with premature shift from symmetric to asymmetric progenitor cell divisions, leading to premature neurogenesis, a depletion of the progenitor pool, and a reduction of the final number of neurons ( Buchman et al., 2010 , Fish et al., 2006 , Kaindl et al., 2010 , Lizarraga et al., 2010 ). In addition, reduced propagation and survival of differentiating neural progenitors have been shown ( Kraemer et al., 2015 ).…”