Rett Syndrome is a devastating neurological disorder diagnosed almost exclusively in girls. Children with Rett Syndrome (RTT) appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.
Although the protein implicated in RTT, MeCP2, is known, its precise function is not. Past experiments have demonstrated that MeCP2, acting like a biological deadbolt, binds to genes that have undergone methylation (a fundamental biological process in which the cell disables genes it doesn't use by modifying them with a methyl group) preventing them from activating. As a result, scientists theorized that MeCP2 was a "long-range gene repressor."
Jaenisch's lab, with RSRF funding, demonstrated that when MeCP2 is disabled in mice, the animals manifest Rett-like symptoms. The next step was to figure out why this happens and what genes MeCP2 targets.
Concurrently, Greenberg, who is also a professor of neurobiology at Harvard Medical School, was studying a central nervous system gene, BDNF, which is highly active in infants aged 6 to 18 months -- the same age that Rett symptoms first appear. This brain derived neurotrophic factor gene is essential for neural plasticity, learning and memory. BDNF is also implicated in other neurological disorders including Huntington's Disease.
Greenberg noted that BDNF constantly flips back and forth between an "on" state, where it rapidly produces protein, and an "off" state, during which it is silent.
"We knew a lot about how it was turned on," says Greenberg, "but we wanted to know what kept it off."
A graduate student in Greenberg's laboratory, Wen Chen, discovered that MeCP2 controlled the "off" state of BDNF, suggesting that BDNF might contribute to the symptoms seen in RTT. The assumption was that once MeCP2 bound to BDNF, the gene would become permanently inactive. Instead, Chen and post-doctoral fellow, Qiang Chang of the Jaenisch lab, discovered a far more dynamic process.
After the BDNF gene is methylated, MeCP2 does indeed bind to it, shutting the gene off -- but only temporarily. If neurons are excited by any kind of environmental stimuli, MeCP2 immediately detaches, and the BDNF gene begins producing protein. When the stimulus disappears, MeCP2 re-attaches to BDNF, again locking the deadbolt until neuronal stimuli start the process again. Greenberg and Jaenisch say they have never before witnessed this kind of process.
"I find this to be an extremely exciting new development. It is particularly gratifying that RSRF support facilitated the Jaenisch study. RSRF's commitment to funding research into the causes of Rett is clearly beginning to pay off. " says Adrian Bird, of the University of Edinburgh, whose lab discovered MeCP2 more than a decade ago. "To me, what's particularly surprising is that DNA methylation appears to be involved with dynamic regulation of this gene. In the past it has been associated with long term inflexible gene silencing." Bird, Chairman of the RSRF Scientific Advisory Board, has a Perspective article published in the same issue of Science. "It might well be that BDNF is a crucial gene that explains some of the symptoms of Rett patients, but we can't be really sure yet."
The investigators theorize that in Rett patients, mutations in MeCP2 impair its ability to regulate BDNF, and that BDNF's subsequent over-expression may cause Rett symptoms. However, Greenberg points out that BDNF is only one of approximately 300 genes that are controlled by neuronal activity, some of which may also be MeCP2 targets.
The next step, says Greenberg, "is to identify other genes that are regulated by MeCP2," which he says can now can be done on a genome-wide scale. Greenberg was recently awarded a grant by RSRF to support his ongoing research.
"The Greenberg and Sun publications will generate unprecedented attention for RTT in the scientific community. RSRF stands poised to capitalize on any breakthroughs that can be translated into clinical applications for RTT patients." says Monica Coenraads, RSRF VP of Research.
Founded in late 1999, RSRF is the world's only organization devoted exclusively to advancing and supporting biomedical research for RTT. To date, RSRF has committed $4.5 million to fund 45 research projects and scientific meetings.
"RSRF's support of this crucial research underscores our commitment to funding high quality science. In 2002, 98 cents of every dollar went directly to our research program. We are determined to increase our financial commitment to equal the momentum generated by these new developments." says Gordon Rich, RSRF President.
For more information on RSRF please visit our website at www.rsrf.org . Investigators interested in joining RSRF's Email broadcast please email monica@rsrf.org with name, institution and area of specialty.
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Science