| Pruning of exuberant axons and dendrites is a widespread mechanism in vertebrates and invertebrates for achieving the mature pattern of neuronal connections. In Drosophila, mushroom body (MB) gamma neurons undergo developmental pruning of their axonal projections in response to the cell-autonomous action of the steroid hormone ecdysone. We have shown that MB axons are pruned through axon degeneration localized to the axon branches, which requires the intrinsic activity of the ubiquitin-proteasome system (UPS), and surrounding glia the for engulfment and degradation of axon fragments.; To extend our understanding of the mechanisms that regulate axon degeneration I conducted two screens to identify new genes involved in developmental axon pruning of MB neurons: (1) a microarray screen to identify genes differentially regulated by ecdysone signaling in MB neurons at the onset of metamorphosis, and (2) a systematic gain-of-function screen in MB neurons for genes that disrupt axon pruning and neuronal morphogenesis. These approaches have provided insight into the mechanisms that regulate developmental pruning and MB morphogenesis. Furthermore, both screens identified boule, a gene encoding an RNA binding protein, as a negative regulator of axon pruning. boule expression is down regulated by ecdysone at the onset of pruning and overexpression of Boule is sufficient to inhibit pruning. Furthermore, Boule function in axon pruning is dependent on its RNA-binding domain.; The striking morphological similarities between axon degeneration during developmental pruning and injury-induced Wallerian degeneration of mature neurons, suggest that they share similar molecular mechanisms. I systematically compared the mechanisms of developmental and injury-induced axon degeneration in flies and mice. I show that expression of mammalian Wlds protein, which inhibits Wallerian degeneration in mammals, inhibits injury-induced axon degeneration in Drosophila. Surprisingly, Wld s expression has no effect on developmental axon degeneration in flies or mice, although it protects the same developing axons against injury-induced degeneration. By contrast, both types of axon degeneration require the cell-autonomous function of the UPS and the glial cell-surface receptor Draper for axon fragmentation and clearance. Thus, the mechanisms regulating developmental and injury-induced axon degeneration differ significantly in early steps, but may converge onto a common execution pathway. |
