Study confirms Rett syndrome begins in neurons

CAMBRIDGE, Mass. — Scientists have known for some time that mutations in a gene named MeCP2 lead to Rett syndrome, a major cause of mental retardation in girls. When they knock out the gene in mice, the mice get the disease. Even though MeCP2 is expressed in various organs throughout the body, researchers suspected that Rett syndrome only results when MeCP2 is mutated in the central nervous system. To test this theory, scientists must study what happens when the gene is either turned on or off only in neurons, something that has proved difficult to do.

Now, a research team led by Whitehead Institute Member Rudolf Jaenisch has provided evidence for the long accepted, but previously unproven theory that Rett syndrome is caused by loss of MeCP2 exclusively in neurons.

Scientists grew mouse embryonic stem cells containing a disabled MeCP2 gene. They then introduced into these cells a non-mutated MeCP2 gene attached to a string of DNA that would assure that this new gene became expressed only in neurons. These stem cells were used to create mice in which MeCP2 was disabled everywhere except in the central nervous system. The mice, consequently, never developed Rett syndrome. As a result, this proves the theory that MeCP2 is only relevant to Rett syndrome in the context of neurons.

“The next step is to put the gene back into the mice after birth in order to test whether treatment of patients after birth could prevent the disease,” says Sandra Luikenhuis, graduate student in Jaenisch’s lab and lead author of the new study, published in the April 20 edition of the journal Proceedings of the National Academy of Sciences. “That’s what we’re working on now.”