Molecular mechanisms regulating local translation during axon growth and guidance

Welshhans, Kristy

Abstract

The long-term goal of this research is to understand the molecular mechanisms underlying the establishment of neuronal connectivity during development. Specifically, this research examines how the growth cone, which is the pathfinding structure of the developing neuron, migrates to and connects with its appropriate targets. Neuronal connectivity is directed via both external and internal cues, which results in the activation of various cellular signaling pathways and ultimately, cytoskeletal reorganization. This proposal focuses on understanding the molecular mechanisms linking cellular signaling and local translation in the developing nervous system. It has only recently been discovered that local translation in axonal growth cones is necessary for the processes of axon growth and guidance. As such, our understanding of local translation is very limited. This study focuses on a multifunctional scaffolding protein, RACK1, which likely provides a critical link between cellular signaling and the regulation of local translation. We have preliminary data that this local translation takes place at point contacts, which are adhesion sites within growth cones that are essential for appropriate axon growth and guidance. Thus, our preliminary data suggests that point contacts are not just adhesion sites, but also critical signaling centers. Here, we hypothesize that point contacts within growth cones serve as a strategic location for targeted local translation and RACK1 is critical to this process. This proposal will provide valuable research opportunities for both undergraduate and graduate students to study fundamental processes that take place during neural development. Using advanced live cell imaging, fluorescent translation reporters, shRNA and axon growth and guidance assays, here we will determine if local translation occurs at point contacts in growth cones, and examine how RACK1 regulates point contact dynamics and axon growth and guidance. Taken together, this research will enable a broad, mechanistic understanding as to how mRNA trafficking and local translation contributes to the establishment of neuronal connectivity, thereby increasing our knowledge about the complex nature of brain development.

Public Health Relevance

This research contributes to our understanding of how neural wiring occurs during development. Specifically, this proposal examines the molecular mechanisms underlying mRNA localization and local translation to determine how it regulates the establishment of neuronal connectivity. This study enables a greater understanding into the complex nature of brain development.