Our brain consists of billions of nerve cells enabling to learn, remember and reason. Every time we think and experience, touch, smell or fear, millions of neurons in our brain becomes active. These nerve cells communicate with each other by chemical and electrical impulses to compute incoming sensory information and integrate it via distinct brain regions. With 20,000 - 25,000 genes in our genome, most also expressed in neurons, there is now little doubt that neurons respond to challenging environments by adjusting the expression of genes for appropriate brain functions. Stress, addiction, learning and disease are all believed to change neuronal gene expression by mechanisms involving gene accessibility without changes in DNA sequences, a process called epigenetics ("above and beyond the gene").
Switching gene expression "on" and "off" is of utmost importance when studying gene function in the adult nervous system. In the early 1990s, scientists described a tetracycline-controlled gene expression systems (Tet systems), which allow the regulation of gene expression by externally applied substances. The Tet-regulated gene expression can be used to analyze involvement of genes for example in cognition in the mouse, as was shown in key studies from 1996. But in spite of the published success, others scientists report some difficulties: in some experiments the full reactivation of Tet-regulated genes failed. Mazahir T. Hasan and colleagues at the Max Planck Institute for Medical Research in Heidelberg have therefore systematically examined individual components of the Tet systems and delineated the necessary conditions for reversible control of gene expression in neurons.
In the June 20th issue of the online, open-access journal PLoS ONE, they report that genes which had been inactive in neurons during early mouse development become functionally silenced in the adult brain. Intriguingly, Hasan and colleagues found that gene silencing in the adult brain can be avoided by making neurons produce high levels of gene-specific activators which facilitate "un-silencing" of previously silenced genes. These findings have important implications in experimental research that makes use of reversible gene expression tools to switch genes on and off. Neuroscientists need such gene switches to investigate the cause-and-effect relationship between gene activity, neuronal physiology, and animal behavior. Hence, this new research is an important step in both the development of highly reliable gene-switches for experimental neuroscience and in our understanding of mechanisms governing gene regulation in the brain. Indeed, the epigenetic mechanisms in charge of switching genes "on" or "off" play an essential role when our brain learns and stores information, and when our brain reacts to injury and disease.
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Mazahir Hasan (corresponding author)
Citation: Zhu P, Aller MI, Baron U, Cambridge S, Bausen M, et al (2007) Silencing and Un-silencing of Tetracycline-Controlled Genes in Neurons. PLoS ONE 2(6): e533. doi:10.1371/journal.pone.0000533
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