Neurons are morphologically complex and highly polarized cells that require tight spatiotemporal regulation of their proteome for proper development, function and survival. mRNA localization is essential in this process allowing precise control of where and when protein products are synthesized and execute their function. Moreover, mounting evidence suggests that neurodevelopmental and neurodegenerative disorders can arise when mRNA localization is impaired. However, the regulation of mRNA localization and local translation in neurons remains poorly understood.
The endosomal system is composed by a heterogeneous and interconnected population of vesicles that carry out the transport of specific cargos throughout the cytoplasm and thus coordinate how neurons integrate, process and transfer information within and between sub-compartments. It has been recently discovered that mRNAs and ribosomes can associate with endosomes in neuronal projections, opening the possibility that endosomal trafficking could also directly control the subcellular proteome by regulating the localization and/or translation of specific mRNAs.
The overall objectives of this project are to investigate the links between the endosomal pathway and subcellular control of protein synthesis in neurons and uncover the associated functions during axonal development. By achieving our research program, we plan to i) identify the mRNAs associated with endosomes and determine whether endosomal trafficking regulates their axonal localization, ii) decipher the roles of the endosomal pathway in the selective translation of axonal mRNAs, iii) determine the molecular mechanisms behind mRNA binding to endosomes and the effects of perturbing them during axon development, and iv) determine if dysregulations of endosomal control of protein synthesis could be directly linked to axonopathies.
