Developing a cell culture system for high-throughput screening of Rett syndrome therapeutics

Rett syndrome is a devastating form of Autism that affects 1/50,000 girls born in the US. Mutations on the gene that encodes for the methyl-DNA binding protein MeCP2 account for more than 90% of the diagnosed cases of Rett syndrome. However, the downstream targets of MeCP2 and the molecular consequences of the identified mutations remain elusive. My laboratory studies the mechanisms that regulate the monogenic and monoallelic expression of olfactory receptor genes in the mouse. Using the MeCP2 knockout mouse model we discovered a very subtle, but extremely significant consequence of MeCP2 deletion; the inappropriate expression of more than one olfactory receptor genes in each olfactory sensory neuron. Using this olfactory receptor gene miss-expression phenotype as a molecular assay, we designed a high throughput screen for small molecules that can reverse the consequences of MeCP2 deletion and therefore can potentially function as Rett syndrome therapeutics. Therefore we propose to use cultured olfactory neurons as ?biosensors? for highthroughput pharmacological screens for Rett syndrome. With the generous support of the Heart grant we will be able to establish the proposed assay.