Duas proteínas importantes para cérebros de tamanhos normais: descoberta pode lançar luz sobre a evolução do tamanho do cérebro humano

sábado, maio 15, 2010

Two Proteins Key for Normal-Sized Brains: Findings Could Shed Light on Evolution of Human Head Size

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)

Neurogenesis is the process through which neurons are created during prenatal development to populate the growing brain. Li-Huei Tsai, director of the Picower Institute and Picower Professor of Neuroscience, found that two proteins -- Cdk5rap2 and pericentrin -- work together to regulate neural growth in the developing brain. Loss of function of these proteins results in human disorders such as primary autosomal recessive microcephaly (MCPH) and Majewski osteodysplastic primordial dwarfism, type II (MOPDII), genetic conditions characterized in part by abnormally small head circumference.

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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Neuron, Volume 66, Issue 3, 386-402, 13 May 2010 | Copyright © 2010 Elsevier Inc. All rights reserved. | 10.1016/j.neuron.2010.03.036

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


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


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.