Cdk5rap2 Interacts with Pericentrin to Maintain the Neural Progenitor Pool in the Developing Neocortex

Abstract

Primary autosomal-recessive microcephaly (MCPH) and Majewski osteodysplastic primordial dwarfism type II (MOPDII) are both genetic diseases that result in decreased brain size at birth. MCPH is thought to arise from alterations in the size of the neural progenitor pool, but the cause of this defect has not been thoroughly explored. We find that one of the genes associated with MCPH, Cdk5rap2, is highly expressed in the neural progenitor pool and that its loss results in a depletion of apical progenitors and increased cell-cycle exit leading to premature neuronal differentiation. We link Cdk5rap2 function to the pericentriolar material protein pericentrin, loss of function of which is associated with MOPDII. Depletion of pericentrin in neural progenitors phenocopies effects of Cdk5rap2 knockdown and results in decreased recruitment of Cdk5rap2 to the centrosome. Our findings uncover a common mechanism, involving aberrations in the neurogenesis program, that may underlie the development of microcephaly in multiple diseases.

Neuronal stem cells in the central nervous system and in human diseases

“…In the mouse brain, Cdk5rap2 is highly expressed in the neural progenitor pool, which accounts for the depletion of RG cells and the increase of cell cycle exit, resulting in premature neuronal differentiation (Megraw et al, 2011). Cdk5rap2 has recently been shown to stimulate microtubule nucleation (Choi et al, 2010) and regulate centriole replication (Barrera et al, 2010) via a tight link to pericentrin (Buchman et al, 2010). In mouse models, ASPM has been shown to be involved in maintaining symmetric divisions of RG cells and in completing cytokinesis (Kouprina et al, 2005;Higgins et al, 2010).…”

Translational potential of human brain organoids

“…Loss‐of‐function mutation in CDK5RAP2 has been implicated in microcephaly, but mouse models failed to reproduce the full spectrum of human phenotypes 39, 40. When brain organoids were generated from microcephaly patients harboring truncating mutations of CDK5RAP2 , they were found to be significantly smaller than the ones generated from controls 27.…”

Interkinetic Nuclear Movement in the Ventricular Zone of the Cortex

“…Both CDK5RAP2 and CENPJ are localized to the centrosomes. In the mouse brain, Cdk5rap2 is highly expressed in the neural progenitor pool, and its loss results in a depletion of apical progenitors and increased cellcycle exit leading to premature neuronal differentiation (Buchman et al 2010). Cdk5rap2 function was further linked to the pericentriolar material protein pericentrin.…”

“…Cdk5rap2 function was further linked to the pericentriolar material protein pericentrin. Depletion of pericentrin in neural progenitor phenocopies the effects Cdk5rap2 knockdown and results in decreased recruitment of Cdk5rap2 to the centrosome (Buchman et al 2010). Pericentrin is mutated in human patients with reduced brain and body size (Seckel syndrome; Griffith et al 2008).…”