Regulating axon guidance through local translation at adhesions

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PROJECT SUMMARY The precise establishment of neuronal connectivity during development is critical for normal nervous system function. This research examines how growth cones, which are the pathfinding structures of the developing neuron, connect with their appropriate targets. External cues regulate neuronal connectivity formation by resulting in the activation of intracellular signaling pathways and ultimately, reorganization of the cytoskeleton and adhesions. This proposal focuses on understanding the molecular mechanisms linking extracellular signaling with intra-axonal local translation in the developing nervous system. Local translation in axonal growth cones is necessary for axon growth and guidance, however our understanding of how local translation functionally directs axon guidance is limited. We recently demonstrated that point contacts, adhesion sites within growth cones, are a strategic location for targeted local translation. Point contact adhesions directly regulate axon guidance by linking the extracellular matrix to the intracellular actin cytoskeleton and providing the force for growth cone movement. Thus, this finding is important because it suggests that local translation of certain mRNAs at adhesions are situated to have a maximal impact on axon guidance. Point contacts are likely a fundamental puzzle piece that has been missing from our understanding of how local translation functionally directs axon guidance. Accordingly, our hypothesis is that local translation of β-actin mRNA is necessary for point contact dynamics, and point contacts are localized organizing nodes for translational regulation. We will test this hypothesis by determining if locally translated β-actin is integrated into point contacts to direct axon guidance (Aim 1) and elucidating the signaling pathway through which extracellular matrix-induced signaling stimulates intra-axonal mRNA translation (Aim 2). Furthermore, we will resolve the suite of mRNAs that are locally translated in response to extracellular matrix proteins, and their relationship to point contacts (Aim 3). Completion of the proposed aims will break new ground by discovering the interactions between the extracellular matrix, point contacts and local translation in the regulation of axon guidance. This research will enable a broad, mechanistic understanding as to how mRNA trafficking and local translation contributes to the establishment of neuronal connectivity, and increase our knowledge about the complex nature of brain development.