ABERRANT ASTROCYTE MATURATION CONTRIBUTES TO RETT SYNDROME PATHOGENESIS
Natasha Pacheco, Leanne Holt, David Crossman, Michelle Olsen.
The University of Alabama at Birmingham, Birmingham, AL.
Rett syndrome (RTT) is an x-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. RTT is characterized by having apparently normal development until 6 to 18 months, when a progressive decline in motor and language functions begins and breathing abnormalities and seizures present. Astrocytes, the most abundant cell type in the central nervous system (CNS), have recently been shown to express MeCP2. Importantly, postnatal re-expression of MeCP2 in astrocytes in globally Mecp2-deficient mice ameliorated many RTT disease symptoms, indicating that deficiencies in astrocytic function contribute to the pathophysiology of RTT. However, the causative mechanisms are currently unknown. Given the broad transcriptional regulatory role of MeCP2, we predict that many astrocytic genes are dysregulated. To test this prediction, we have utilized RNA-Seq analysis to examine global gene expression changes in enriched cortical astrocytes compared to whole cortex tissue from symptomatic Mecp2-deficient mice compared to wild-type (WT) littermate controls. We have identified over 1,700 significant and differentially expressed genes in cortical astrocytes. Pathway analysis in our cortical astrocyte dataset has identified disrupted pathways involved in inflammation and metabolism as well as gastrointestinal, neurological, and immunological diseases. Furthermore, molecular and cellular functions associated with proper astrocytic maturation were also identified as being disrupted. Our current work is directed at understanding when in the disease process these changes occur. Through the identification of key groups of astrocytic genes, proteins, and pathways, we can begin to tease apart the mechanisms in which astrocytes contribute to RTT pathogenesis, possibly identifying new and much needed therapeutic targets for RTT patients.