Genetic programmes for dendrite regrowth after pruning in Drosophila - mechanistic and functional aspects

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The establishment of the mature neuronal connectivity during development often occurs in distinct phases of progressive and regressive events. In particular, connectivity can be remodeled through regulated degeneration of neurites and synapses, a process known as pruning. In such cases, neurons can regrow new neurites or synapses with altered connectivity. While several examples of such remodeling have been described from invertebrates to mammals, little is known about how pruning and regrowth are coordinated at the molecular level and what the consequences of failed pruning and/or regrowth are for neuronal function. A well-suited model to study pruning mechanisms are Drosophila peripheral sensory neurons, which prune their larval sensory dendrites at the onset of metamorphosis and later regrow them with adult-specific morphology. While the molecular mechanisms underlying the initial dendrite pruning are beginning to emerge, little is known about dendrite regrowth. We could previously show that dendrite pruning is regulated at the level of translation initiation, apparently in order to limit protein biosynthesis. In contrast, we found that molecular pathways promoting protein biosynthesis – the Target of Rapamycin (TOR) pathway, and also mRNA splicing, are required for dendrite regrowth after pruning in an apparently specific manner. This raises the question as to whether a global upregulation of protein biosynthesis is sufficient to promote dendrite regrowth, or whether specific mRNAs must be spliced correctly and translated. In addition, it is not clear how dendrite regrowth is linked to adult sensory neuron function. Here, we propose to systematically identify the genetic basis for dendrite regrowth after pruning. To this end, we will (1) perform candidate RNAi screens to identify the regulatory gene networks for dendrite regrowth; (2) identify downstream targets of TOR and splicing factors using candidate approaches and RNAseq, respectively and (3) develop functional behavioral assays for adult sensory neuron function to assess the effects of regrowth (and also pruning) defects. Our project will provide important insights into the interplay between pruning, regrowth, and neuronal function.