Title

Cell-specific regulation of MeCP2 expression in Drosophila Astrocytes

Presentation Type

Presentation

Abstract

Sporadic mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett Syndrome a severe, neurodevelopmental disorder characterized by loss of motor and language skills, unusual stereotyped movements, autistic features, anxiety, and aggression. Duplication of the MeCP2 gene in males results in mental retardation, autistic behaviors, stereotyped hand movements and anxiety-related behaviors. The population prevalence of MeCP2 mutations is unknown. In addition, the mechanism by which mutations in the MeCP2 protein, MeCP2 protein levels, or whether neuronal or glial MeCP2 expression changes cause disease phenotypes is unclear.

Astrocytes are a type of glia found throughout the brain. Astrocytes provide neurons with nutrients, guide their development, and maintain signaling conditions at synapses. Because interactions between glia and neurons are essential for many critical brain functions, we proposed that MeCP2 activity in astroctyes causes gene expression changes that alter the function of neighboring neurons. Using the UAS-Gal4 binary expression system we can express wildtype and mutant human MeCP2 (hMeCP2) protein in Drosophila astrocytes. We demonstrated that wildtype hMeCP2 causes sleep and aggression behavioral changes. Using MeCP2 antibody labeling, we can visualize MeCP2 expression in specific neurons and glial cells in the adult brain.

High levels of MeCP2 expression were expected in astrocytes throughout the brain. Instead, expression was reduced and restricted to the subesophageal ganglion (SOG) region. The reduction was present in brains expressing the wildtype and mutant MeCP2R106W allele, but not the MeCP2Δ166 allele. The MeCP2Δ166 allele lacks the N-terminus and methyl-binding domain. We utilized qPCR on transcripts of whole brains expressing different hMeCP2 forms. Wildtype MeCP2 mRNA was present in brains exhibiting reduced expression indicating that reduced MeCP2 protein expression is not due to a transcription defect. A mechanism that regulates MeCP2 expression would be clinically relevant to MeCP2 disorders. My results may be extrapolated to human beings via conserved cellular mechanisms.

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Apr 12th, 9:40 AM Apr 12th, 10:00 AM

Cell-specific regulation of MeCP2 expression in Drosophila Astrocytes

UC 331

Sporadic mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett Syndrome a severe, neurodevelopmental disorder characterized by loss of motor and language skills, unusual stereotyped movements, autistic features, anxiety, and aggression. Duplication of the MeCP2 gene in males results in mental retardation, autistic behaviors, stereotyped hand movements and anxiety-related behaviors. The population prevalence of MeCP2 mutations is unknown. In addition, the mechanism by which mutations in the MeCP2 protein, MeCP2 protein levels, or whether neuronal or glial MeCP2 expression changes cause disease phenotypes is unclear.

Astrocytes are a type of glia found throughout the brain. Astrocytes provide neurons with nutrients, guide their development, and maintain signaling conditions at synapses. Because interactions between glia and neurons are essential for many critical brain functions, we proposed that MeCP2 activity in astroctyes causes gene expression changes that alter the function of neighboring neurons. Using the UAS-Gal4 binary expression system we can express wildtype and mutant human MeCP2 (hMeCP2) protein in Drosophila astrocytes. We demonstrated that wildtype hMeCP2 causes sleep and aggression behavioral changes. Using MeCP2 antibody labeling, we can visualize MeCP2 expression in specific neurons and glial cells in the adult brain.

High levels of MeCP2 expression were expected in astrocytes throughout the brain. Instead, expression was reduced and restricted to the subesophageal ganglion (SOG) region. The reduction was present in brains expressing the wildtype and mutant MeCP2R106W allele, but not the MeCP2Δ166 allele. The MeCP2Δ166 allele lacks the N-terminus and methyl-binding domain. We utilized qPCR on transcripts of whole brains expressing different hMeCP2 forms. Wildtype MeCP2 mRNA was present in brains exhibiting reduced expression indicating that reduced MeCP2 protein expression is not due to a transcription defect. A mechanism that regulates MeCP2 expression would be clinically relevant to MeCP2 disorders. My results may be extrapolated to human beings via conserved cellular mechanisms.