How are axons guided to their targets in the developing nervous system? (2016–2018)
For the brain to function correctly it must be wired correctly, and many neurodevelopmental disorders are likely the result of wiring defects. Axon guidance occurs primarily via the sensing of molecular cues in the environment, and a critical mechanism by which such cues are believed to act is via concentration gradients. However we do not have a quantitative understanding of how axons actually respond to concentration gradients. It is thus impossible to know whether current explanations for axon guidance events in vivo are actually sufficient to generate the axon trajectories observed. To address this problem we will first use novel microfluidics technologies to create precisely controlled molecular gradients in vitro, measure axon trajectories over long periods of time as gradient parameters are systematically varied, and develop computational models to quantitatively explain the key properties of these trajectories. Second, we will computationally model the spatiotemporal distribution of guidance cues believed to steer axons in two paradigmatic model systems, the development of the corpus callosum and of thalamocortical connections. We will then test whether the quantitative framework for understanding axon trajectories developed above accurately predicts the observed behaviour, both in the wild type and in mutants where particular cues have been disrupted. This project will provide the first direct way of quantitatively predicting axon trajectories in vivo. This will allow the adequacy of current explanations for guidance in vivo to be quantitatively tested for the first time. We predict that mechanisms additional to gradients will be required, thus demanding new conceptual frameworks for understanding how axon guidance occurs in vivo. This provides a key first step towards a paradigm shift in our understanding of how brains become wired up.