ScienceDaily (May 13, 2010) — In work that may one day correct or prevent genetic conditions tied to smaller-than-normal brains and shed light on the evolution of human head size, researchers at MIT's Picower Institute for Learning and Memory analyzed the interaction of two proteins key to brain development.
New research into two proteins key to brain development may one day correct or prevent genetic conditions tied to smaller-than-normal brains and shed light on the evolution of human head size. (Credit: iStockphoto/Stephen Kirklys)
An understanding of these rare genetic disorders may offer insight into one of the most striking differences between us and our closest living relatives: brain size and cognitive ability.
The researchers show that Cdk5rap2 and pericentrin interact with one another to regulate proliferation of neural progenitor cells that give rise to the brain layer called the neocortex. Pericentrin recruits Cdk5rap2 to structures within the neural progenitor cells, and loss of Cdk5rap2 results in decreased cell proliferation.
"Given the link between head circumference, intelligence deficits and psychiatric disorders, these findings have implications for our understanding of how abnormalities in brain development can play a role in a number of diseases," said Tsai, a Howard Hughes Medical Institute investigator and the director of the neurobiology program at the Broad Institute's Stanley Center for Psychiatric Research. In addition to leading to potential treatments for MCPH and MOPDII, the work may also shed light on the increase in brain size during human evolution.
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Cdk5rap2 Interacts with Pericentrin to Maintain the Neural Progenitor Pool in the Developing Neocortex
Joshua J. Buchman,Huan-Chung Tseng,Ying Zhou,Christopher L. Frank,Zhigang Xie,Li-Huei Tsai
Highlights
Cdk5rap2 knockdown results in depletion of neural progenitors
Cdk5rap2 knockdown alters neural progenitor pool composition
Knockdown of pericentrin phenocopies Cdk5rap2 knockdown
Pericentrin recruits Cdk5rap2 to the centrosome in neural progenitor cells
Summary
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.
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