Discovery and analysis of genes that govern axon guidance in the developing nervous system

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Nervous system function relies upon patterned development of neurons and controlled establishment of synaptic connections. Axons of developing neurons are guided by instructive cues to their appropriate target areas, where they then select their correct synaptic partners. The molecular and cellular mechanisms by which this occurs are incompletely understood. In this Discovery Grant we will use genetic studies in the fruit fly Drosophila to understand how axons are guided by these cues and how they distinguish appropriate targets from inappropriate ones. This is a central issue in developmental neurobiology, and one for which Drosophila is ideally suited as a model system. Despite past successes, forward genetic screening in Drosophila can be limited by technical challenges and by genetic redundancies that obscure the detection of mutant phenotypes. Such limitations have undoubtedly left many genes and molecular pathways remaining to be described. In an alternative and innovative approach, we have used a gene misexpression system to identify genes and molecular pathways that can influence axon guidance. We recently reported the results of a screen in which we identified 42 candidates capable of influencing axon guidance, causing a range of effects from misprojections of axon subsets to severe nervous system disorganization. In this Discovery Grant, our overall hypothesis is that characterization of genes found in our screen will reveal new molecular pathways controlling axon guidance. We propose three main research Aims. First, we will unequivocally identify the genes responsible for observed misexpression phenotypes, and thereby discover molecules with the potential to act in axon guidance (Aim 1). Second, we will determine whether these genes are expressed in developing neurons and we will use loss-of-function approaches in vivo to determine if these genes are required for axon guidance (Aim 2). Finally, we will investigate the mechanisms by which selected genes affect axon guidance (Aim 3). Our overall goal is to explain at a molecular level the principles upon which nervous systems are organized during development, and to provide a world-class training environment for graduate students in neuroscience.