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Newly discovered mechanisms control the number of cerebral cells at the embryonic development stage
13 February 2009
A group of researchers of the Instituto de Investigaciones Biomédicas Alberto Sols (a mixed centre of the Consejo Superior de Investigaciones Científicas and the Universidad Autónoma de Madrid) have discovered the participation of a protein denoted DREAM in the activation of genes that are necessary for the progenitor cells of embryonic brains to differentiate themselves into astrocytes. The study, published in the latest June issue of the prestigious magazine The Journal of Neuroscience [28(26):6703– 6713 (2008)], has been directed by Dr. Mario Vallejo, and constitutes part of the doctoral thesis of Beatriz Cebolla and Antonio Fernández-Pérez, co-authors of the article.
Studies previously conducted in Dr. Vallejo's laboratory put forth that progenitor cells of the embryonic cerebral cortex are capable of responding to particular extracellular signals by increasing the levels of a second intracellular messenger called cyclic AMP. This second messenger is capable of activating mechanisms that alter the genetic program of progenitor cells and induce them to differentiate into astrocytes. Working in collaboration with Dr. Alfonso Araque and Dr. Gertrudis Perea of the Instituto Cajal de Madrid (Consejo Superior de Investigaciones Científicas), also co-authors of the study, the researchers determined that the cyclic AMP produced activates the entry of calcium from the extracellular environment into the cell, and that calcium is responsible for the genetic effects of cyclic AMP. Among others, this discovery suggested that a possible mechanism by which calcium could mediate cyclic AMP effects over the expression of genes crucial for the differentiation of astrocytes could be through the activation of the DREAM protein. It is already well known that DREAM is a transcription factor, which means that it is a protein capable of directly regulating the expression of certain genes, and that its activity is regulated by calcium.
The research team discovered that DREAM regulates the activation of essential genes for the differentiation of astrocytes. When DREAM is not present, progenitor cells can not differentiate into astrocytes after being brought in contact with signals that act through the production of cyclic AMP. Nevertheless, these cells do not lose their differentiation capability, since they can transform into astrocytes as a response to different signals that do not require the production of this second messenger.
The research group managed by Dr. Vallejo observed that during the postnatal period, a period during which most astrocytes are generated, the brains of mice lacking DREAM contained an abnormally low number of these cells. Surprisingly, while gathering this data, the researchers noticed that the brains of mice lacking DREAM contained an abnormally high number of neurons. Taking into consideration that during the development of the brain, the neural progenitors produce neurons before producing astrocytes, these results indicate that DREAM takes part in the mechanism that blocks the production of neurons while activating the production of astrocytes. In the brains of mice lacking DREAM, compensation mechanisms take place that ensure that the adult animals would produce an abnormally high number of astrocytes during their lifetime, reinforcing the theory that the relation between the number of neurons and astrocytes has a great functional importance. Therefore, the lack of DREAM produces brains with a higher number of cells.
The authors of the study have emphasized the importance of the cyclic AMP-calcium-DREAM system in the mechanisms responsible for the production of astrocytes and controlling the number of neurons and astrocytes produced from neuronal progenitors during the development of the brain.
Images taken using fluorescence microscope showing on the left, the nuclei of the cells in a determined region of the brain of a normal mouse in blue, and to the right, one lacking DREAM protein. In these images the astrocytes can be distinguished by the emission of red fluorescence, by their prolongations and their star shape. It can be seen that the number of astrocytes in the brain of the mouse lacking in DREAM is higher.