The brain relies for its function on a complex pattern of axonal connections that are initially set up during development. The broad long-term goal of the project is to understand molecular signaling mechanisms that underly the process of pathfinding required for axons to grow toward their correct targets. The current proposal focuses particularly on RNA-based mechanisms, which have not been characterized extensively in the axon.
Aim 1 builds on our recent work showing that the transmembrane 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 surface receptor with the translation machinery leads to a generalizable model for extracellular regulation and localization of translation, based on a transmembrane translation regulation complex. Here we propose further studies to survey how general this phenomenon may be for different classes of receptor, focusing on receptors involved in neural development. Identification of this novel regulatory mechanism also raises interesting questions we will address regarding molecular components and interactions involved in the complex.
Aim 2 extends our work which previously identified RNA-based mechanisms that can regulate protein expression within spinal commissural axons as they navigate past their well characterized intermediate guidance target, the floor plate of the spinal cord. We have identified RNA-binding proteins in the CPEB family that are involved in spinal commissural neuron pathfinding. We propose further studies of the functions of these RNA-binding proteins in axon guidance, using both in vitro and in vivo functional systems. We also propose studies of the downstream target mRNAs bound by these proteins, which will yield insight into their network of regulatory interactions. While our work focuses primarily on the basic biology of neuron development, it has broad implications for health research. Correct axon pathfinding is required for normal neural development, and RNA-based mechanisms are known to contribute to diseases such as mental retardation. Also, a major health problem is created by inability of adult neurons to regenerate, and ultimately the study of developmental pathfinding is likely to contribute to strategies for axon regeneration. More broadly, our work on the neuron provides a model to uncover fundamental principles with very general implications for biomedical research.
Our studies are designed to understand new molecular and cellular mechanisms used by neurons to set up the complex pattern of connections that is required for normal functioning of the brain. When these developmental mechanisms do not proceed properly, this can lead to diseases such as mental retardation. Also, a major health problem is created by the inability of adult neurons to regenerate following injury or degeneration, and ultimately the study of developmental axon growth and pathfinding mechanisms is likely to contribute to strategies for neural regeneration and repair.
|Preitner, Nicolas; Quan, Jie; Nowakowski, Dan W et al. (2014) APC is an RNA-binding protein, and its interactome provides a link to neural development and microtubule assembly. Cell 158:368-82|
|Hancock, Melissa L; Preitner, Nicolas; Quan, Jie et al. (2014) MicroRNA-132 is enriched in developing axons, locally regulates Rasa1 mRNA, and promotes axon extension. J Neurosci 34:66-78|
|Preitner, Nicolas; Quan, Jie; Flanagan, John G (2013) This message will self-destruct: NMD regulates axon guidance. Cell 153:1185-7|