The Molecular Regulation of Dendritic Arbor Shape During Development and Disease

The brain is composed of a network of neural cells which have elaborate cellular structures, especially their dendritic arbors. The correct function of neural networks requires the development of specific dendritic arbor shapes, and altered shapes leads to neural dysfunction. Therefore, understanding the molecules which specify dendritic arbor shapes during development is paramount to understanding how dendritic arbors are misshapen during disease. A complex array of genetic factors regulates dendritic arbor morphology. Therefore, using the Drosophila dendritic arborization (da) neurons, we performed a candidate-based genetic screen to identify molecules associated with neurodegenerative disease and brain aging which can regulate dendritic arbor morphology. Among the many screen hits, we discovered a role of the double-bromodomain and extra terminal (BET) family proteins in regulating dendrite arbor complexity and mechanosensory function. Our results identify a novel role for BET family proteins in regulating dendrite morphology, and a possible separation of developmental pathways specifying neural cell morphology and ion channel expression. Since the BET proteins are known to bind acetylated histone tails, these results also suggest a role of epigenetic histone modifications, and the `histone code,' in regulating dendrite morphology. Finally, we developed a system to study how the expression of disease related molecules can impact mature, already formed, dendritic arbors. Our results indicate that expression of pathogenetic polyglutamine proteins cause a progressive retraction of dendritic branches. This system can be used to study how dendritic arbors are maintained throughout life, and how this maintenance is disrupted during disease