Development of brain circuitry is affected in Rett syndrome and Autism Spectrum Disorder (ASD). Rett syndrome is caused by mutations in the MECP2 gene while ASD is associated with mutations in hundreds of different genes. Genes function by making RNA that is then "translated" into proteins. We discovered that the MECP2 gene makes RNA in human stem cells but it is not stable and is actively degraded. The ability to translate MECP2 RNA into MECP2 protein is also inhibited in stem cells. These two layers of regulation ensure that stem cells do not make too much MECP2 protein until they mature into nerve cells. We predict that many ASD risk genes are regulated in the same manner as MECP2 in stem cells because these RNAs would otherwise promote premature differentiation into nerve cells. We propose to expand our MECP2 gene findings into deciphering a more comprehensive understanding of RNA regulation in human stem cells as they develop into nerve cells. In OBJECTIVE 1 we will define changes in RNA translation. Our experiments will identify which RNAs are making proteins in stem cells and neurons by associating with factories called ribosomes. We will discover how translation of ASD risk genes is controlled and identify proteins that are misregulated in Rett syndrome nerve cells. In OBJECTIVE 2 we will define changes in RNA stability. Our experiments will identify which RNAs are rapidly destroyed in stem cells but not in nerve cells. We will discover how the RNA is targeted for degradation in stem cells, and how it is protected in nerve cells. In both aims, we will test the ability of RNA from ASD risk genes to promote stem cell differentiation or nerve cell maturation. The expected outcomes will be the elucidation of RNA regulation of genes that can be applied to improve directed differentiation of stem cells for regenerative medicine, and may unveil misregulated proteins for future drug development.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
