View Program - 63rd Annual Drosophila Research Conference

One of the most extraordinary characteristics of the nervous system is the complexity of its neural circuits. Although there are many mechanisms involved in shaping the pattern of these connections, one of the most important events is the guidance of axons to their specific targets. Model organism research in the past several decades has advanced our understanding of the function of numerous guidance cues, their receptors and their underlying signaling cascades. More recently it has become clear that after functional circuits have been established, many neurons continue to express developmental guidance cues. The expression of these genes in the adult indicates that there are likely additional roles for them beyond the initial phase of neuronal process outgrowth, growth cone navigation and target innervation.

To test this hypothesis, we performed an RNAi screen against axon guidance genes expressed in the adult nervous system. Using available databases, 151 axon guidance genes were identified that are expressed in the adult Drosophila nervous system. 44 genes were prioritized based on their higher expression profiles and previously known roles in neuronal pathfinding. We knocked down the expression of each of these genes using spatial and temporal control of the GAL4-UAS system and identified 15 genes that are required for adult survival. Knockdown of these 15 guidance cues also caused motility defects.

To understand the impact of axon guidance gene knockdown at a cellular level, we examined well-established circuits such as the olfactory system and motoneuron circuits in adult Drosophila. Knocking down Fasciclin-3, an Ig containing homophilic cell adhesion molecule, led to neuronal death in the adult olfactory system. This phenotype was rescued by overexpressing p35, an anti-apoptotic protein. Knocking down Semaphorins and Plexins, members of the canonical repulsive guidance signalling pathway, resulted in loss of motoneurons. Currently, we are examining the impact of Semaphorin/ Plexin double knockdowns to understand the cellular and molecular mechanism responsible for these phenotypes. We are also examining the impact of Semaphorin/ Plexin knockdown on the olfactory circuit and neuromuscular junctions.

Taken together, we believe that the continued expression of axon guidance genes in the adult is critical for the maintenance of neural circuits in the mature nervous system.

Developmental axon guidance cues are critical for adult neuronal survival and function