@article {2679, title = {Genomic analysis of Drosophila neuronal remodeling: a role for the RNA-binding protein Boule as a negative regulator of axon pruning.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {28}, year = {2008}, month = {2008 Jun 11}, pages = {6092-103}, abstract = {

Drosophila mushroom body (MB) gamma neurons undergo axon pruning during metamorphosis through a process of localized degeneration of specific axon branches. Developmental axon degeneration is initiated by the steroid hormone ecdysone, acting through a nuclear receptor complex composed of USP (ultraspiracle) and EcRB1 (ecdysone receptor B1) to regulate gene expression in MB gamma neurons. To identify ecdysone-dependent gene expression changes in MB gamma neurons at the onset of axon pruning, we use laser capture microdissection to isolate wild-type and mutant MB neurons in which EcR (ecdysone receptor) activity is genetically blocked, and analyze expression changes by microarray. We identify several molecular pathways that are regulated in MB neurons by ecdysone. The most striking observation is the upregulation of genes involved in the UPS (ubiquitin-proteasome system), which is cell autonomously required for gamma neuron pruning. In addition, we characterize the function of Boule, an evolutionarily conserved RNA-binding protein previously implicated in spermatogenesis in flies and vertebrates. boule expression is downregulated by ecdysone in MB neurons at the onset of pruning, and forced expression of Boule in MB gamma neurons is sufficient to inhibit axon pruning. This activity is dependent on the RNA-binding domain of Boule and a conserved DAZ (deleted in azoospermia) domain implicated in interactions with other RNA-binding proteins. However, loss of Boule does not result in obvious defects in axon pruning or morphogenesis of MB neurons, suggesting that it acts redundantly with other ecdyonse-regulated genes. We propose a novel function for Boule in the CNS as a negative regulator of developmental axon pruning.

}, keywords = {Animals, Antigens, Axons, CD8, Developmental, Drosophila, Drosophila Proteins, Ecdysone, Gene Expression Regulation, Genetically Modified, Genomics, Green Fluorescent Proteins, Larva, Microarray Analysis, Mushroom Bodies, Mutation, Neurons, Receptors, RNA-Binding Proteins, Steroid}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0677-08.2008}, author = {Hoopfer, Eric D and Penton, Andrea and Watts, Ryan J and Luo, Liqun} } @article {2680, title = {Wlds protection distinguishes axon degeneration following injury from naturally occurring developmental pruning.}, journal = {Neuron}, volume = {50}, year = {2006}, month = {2006 Jun 15}, pages = {883-95}, abstract = {

Axon pruning by degeneration remodels exuberant axonal connections and is widely required for the development of proper circuitry in the nervous system from insects to mammals. Developmental axon degeneration morphologically resembles injury-induced Wallerian degeneration, suggesting similar underlying mechanisms. As previously reported for mice, we show that Wlds protein substantially delays Wallerian degeneration in flies. Surprisingly, Wlds has no effect on naturally occurring developmental axon degeneration in flies or mice, although it protects against injury-induced degeneration of the same axons at the same developmental age. By contrast, the ubiquitin-proteasome system is intrinsically required for both developmental and injury-induced axon degeneration. We also show that the glial cell surface receptor Draper is required for efficient clearance of axon fragments during developmental axon degeneration, similar to its function in injury-induced degeneration. Thus, mechanistically, naturally occurring developmental axon pruning by degeneration and injury-induced axon degeneration differ significantly in early steps, but may converge onto a common execution pathway.

}, keywords = {Animals, Axons, Developmental, Drosophila, Drosophila Proteins, Gene Expression Regulation, Genetically Modified, Inbred C57BL, Mice, Nerve Tissue Proteins, Wallerian Degeneration}, issn = {0896-6273}, doi = {10.1016/j.neuron.2006.05.013}, author = {Hoopfer, Eric D and McLaughlin, Todd and Watts, Ryan J and Schuldiner, Oren and O{\textquoteright}Leary, Dennis D M and Luo, Liqun} } @article {2682, title = {Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system.}, journal = {Neuron}, volume = {38}, year = {2003}, month = {2003 Jun 19}, pages = {871-85}, abstract = {

Axon pruning is widely used for the refinement of neural circuits in both vertebrates and invertebrates, and may also contribute to the pathogenesis of neurodegenerative diseases. However, little is known about the cellular and molecular mechanisms of axon pruning. We use the stereotyped pruning of gamma neurons of the Drosophila mushroom bodies (MB) during metamorphosis to investigate these mechanisms. Detailed time course analyses indicate that MB axon pruning is mediated by local degeneration rather than retraction and that the disruption of the microtubule cytoskeleton precedes axon pruning. In addition, multiple lines of genetic evidence demonstrate an intrinsic role of the ubiquitin-proteasome system in axon pruning; for example, loss-of-function mutations of the ubiquitin activating enzyme (E1) or proteasome subunits in MB neurons block axon pruning. Our findings suggest that some forms of axon pruning during development may share similarities with degeneration of axons in response to injury.

}, keywords = {Animals, Axons, Biological, Cell Adhesion Molecules, Cysteine Endopeptidases, Cytoskeletal Proteins, Cytoskeleton, Cytosol, Drosophila, Endocytosis, Endopeptidases, Gene Expression, Ligases, Metamorphosis, Microtubules, Multienzyme Complexes, Mutation, Nerve Degeneration, Neurons, Proteasome Endopeptidase Complex, Saccharomyces cerevisiae, Synapses, Transfection, Ubiquitin, Ubiquitin-Activating Enzymes, Ubiquitin-Protein Ligases}, issn = {0896-6273}, author = {Watts, Ryan J and Hoopfer, Eric D and Luo, Liqun} }