The Rett gene -- a rogue activator

“Loss of function of the MeCP2 gene causes Rett syndrome,” said Maria Chahrour, a BCM graduate student and first author of the report. Doubling or tripling MeCP2 levels causes other neurological disorders. To better understand the protein, the scientists decided to study mice that either lacked MeCP2 or had too much of it.

They dissected the hypothalamus in both kinds of mice and looked at changes in the genes compared to the same genes in normal mice.

“There are thousands of genes changed by MeCP2,” said Chahrour. In both the mice who had no MeCP2 and those who had too much of the dysfunctional gene, they found changes in expression of thousands of genes. Surprisingly, they found that in at least 85 percent of the genes, MeCP2 turned the gene on. In fact, they found that it associates with CREB1, another gene tasked with turning on genes.

Interestingly, although the two diseases share many features, having no protein versus having too much caused opposite effects on gene expression, suggesting again that “the symptoms are those of an unhappy neuron,” said Zoghbi. Yet as the MeCP2 studies show, these symptoms can have different causes. That fact may mean that what outwardly appears to be the same disease could have very different beginnings and require wholly different treatments.

“Because MeCP2 regulates thousands of genes, it does not make sense to target each of them individually in designing treatments,” Chahrour said. “We are going to have to find a therapeutic strategy that can bypass MeCP2 and restore the normal order in the brain,” she said.

Others who took part in this work include Sung Yun Jung, Chad Shaw and Jun Qin of BCM and Xiaobo Zhou and Stephen T. C. Wong of The Methodist Hospital Research Institute and Weill Cornell College of Medicine.

Funding for this work comes from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development Mental Retardation and Developmental Disabilities Research Center, the International Rett Syndrome Foundation and the Simons Foundation.

When the embargo lifts, the full article can be found at www.sciencemag.org