Research Awards
Michael Greenberg, Ph.D.
Children's Hospital Boston
"Neuronal Activity-Dependent Regulation of MeCP2"
2-Year Award: $100,000
Research Sponsor: The Massachusetts Rett Syndrome Association
Final Report (November 2005)
Mutation of the MECP2 gene has been found to result in 80-85% of Rett Syndrome (RTT) cases, and the protein encoded by this gene is thought to function to suppress gene activation in neurons. We have found that MeCP2 acts to inhibit expression of the Bdnf gene, which encodes a secreted protein capable of regulating neuronal survival and function. In response to neuronal firing, MeCP2 is modified by phosphorylation and is released from the Bdnf gene. These results suggest that MeCP2 acts to regulate genes induced by neuronal activity, and dysregulation of this function may contribute to RTT disease. However, the sites of phosphorylation on MeCP2 were unknown. To begin to address the role of MeCP2 phosphorylation in both normal development and disease, we have identified a number of novel sites of phosphorylation on the MeCP2 protein. One phosphorylation site was found to be induced in response to neuronal activity. Furthermore, mutation of this site interfered with the normal regulation of the Bdnf gene. These studies have provided an increased understanding of MeCP2 function in neurons, and further study of this regulatory mechanism may ultimately provide new opportunities for the development of RTT therapeutics.
Michael Greenberg, Ph.D.Children's Hospital Boston
"Neuronal Activity-Dependent Regulation of MeCP2"
2-Year Award: $100,000
Research Sponsor: The Massachusetts Rett Syndrome Association
Final Report (November 2005)
Mutation of the MECP2 gene has been found to result in 80-85% of Rett Syndrome (RTT) cases, and the protein encoded by this gene is thought to function to suppress gene activation in neurons. We have found that MeCP2 acts to inhibit expression of the Bdnf gene, which encodes a secreted protein capable of regulating neuronal survival and function. In response to neuronal firing, MeCP2 is modified by phosphorylation and is released from the Bdnf gene. These results suggest that MeCP2 acts to regulate genes induced by neuronal activity, and dysregulation of this function may contribute to RTT disease. However, the sites of phosphorylation on MeCP2 were unknown. To begin to address the role of MeCP2 phosphorylation in both normal development and disease, we have identified a number of novel sites of phosphorylation on the MeCP2 protein. One phosphorylation site was found to be induced in response to neuronal activity. Furthermore, mutation of this site interfered with the normal regulation of the Bdnf gene. These studies have provided an increased understanding of MeCP2 function in neurons, and further study of this regulatory mechanism may ultimately provide new opportunities for the development of RTT therapeutics.