All ETDs from UAB

Advisory Committee Chair

Michelle L Olsen

Advisory Committee Members

Rita Cowell

Jeremy Day

Alan Percy

Lucas Pozzo-Miller

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Rett syndrome (RTT) is caused by mutations in the gene encoding the transcriptional modulator, Methyl-CpG-Binding Protein 2 (MeCP2). RTT is characterized by motor, behavioral and physiological deficits. MECP2 mutations are associated with other disorders such as autism, schizophrenia, and intellectual disability, underscoring the important role of MeCP2 for typical brain function. Much of our understanding of MeCP2 function is derived from transcriptomic studies carried out over the last 10 years with the general assumption that alterations in the transcriptome correlate with proteomic changes. Advances in mass spectrometry-based proteomics have facilitated recent interest in the examination of global protein expression. In the current dissertation, we performed the first comprehensive transcriptome-proteome comparison in one of the most commonly utilized murine models of RTT to elucidate the pathophysiology of RTT, identify potential therapeutic targets, and further our understanding of MeCP2 function. This study confirmed previous works regarding mRNA expression patterns in Mecp2-deficient animals, identified hundreds of novel protein targets, and support the notion that RTT is a disease that affects all central nervous system (CNS) cell types. Of particular interest, gene and protein analyses indicated deficits in astrocyte maturation and morphology. These findings were confirmed by performing RNA-sequencing in isolated astrocyte populations across all stages of early postnatal development through young adulthood in wild-type (WT) and Mecp2-deficient mice. In WT mice, the most robust changes in differential gene expression occurred between the second and fourth postnatal week. This postnatal astrocytic maturation period is critical for regulating synaptogenesis, and necessary to carry out a broad range of functions crucial for CNS homeostasis. During this time frame, pathway analysis of WT astrocytes identified pathways enriched in cellular development and morphology, ion channels/transporters and cholesterol metabolism. In contrast, Mecp2-deficient astrocytes contained pathways enriched in extracellular matrix (ECM) proteins and JAK-STAT signaling. Taken together, these data suggest aberrant regulation of astrocytic maturation processes in Mecp2-deficient astrocytes, effects observed early in postnatal development. Through an improved understanding of postnatal astrocyte maturation, better therapeutics can be developed to treat RTT individuals early in development.

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