Signal Transduction in Axon Guidance

The brain relies for its function on a complex pattern of axonal connections thatare initially set up during development. The broad long-term goal of the project is to understand molecularsignaling mechanisms that underly the process of pathfinding required for axons to grow toward theircorrect targets. The current proposal focuses particularly on RNA-based mechanisms, which have notbeen characterized extensively in the axon. Aim 1 builds on our recent work showing that thetransmembrane axon guidance receptor DCC physically associates with translation initiation machinery,including eIFs and ribosomal subunits. This finding of functional and physical association of a cell surfacereceptor with the translation machinery leads to a generalizable model for extracellular regulation andlocalization of translation, based on a transmembrane translation regulation complex. Here we proposefurther studies to survey how general this phenomenon may be for different classes of receptor, focusingon receptors involved in neural development. Identification of this novel regulatory mechanism also raisesinteresting questions we will address regarding molecular components and interactions involved in thecomplex. Aim 2 extends our work which previously identified RNA-based mechanisms that can regulateprotein expression within spinal commissural axons as they navigate past their well characterizedintermediate guidance target, the floor plate of the spinal cord. We have identified RNA-binding proteinsthat are involved in spinal commissural neuron pathfinding. We propose further studies of the functions ofthese RNA-binding proteins in axon guidance, using both in vitro and in vivo functional systems. We alsopropose studies of the downstream target mRNAs bound by these proteins, which will yield insight intotheir network of regulatory interactions. While our work focuses primarily on the basic biology of neurondevelopment, it has broad implications for health research. Correct axon pathfinding is required for normalneural development, and abnormalities of RNA-based mechanisms are known to contribute to diseasesincluding developmental disabilities.