Axonal miRNAs in the development and function of neuron connectivity: intra-axon and inter-neuronal actions (360G-Wellcome-210193_Z_18_Z)

Brain function depends on the correct formation, maintenance and constant changes of neuronal circuits. Among the multiple signaling pathways regulating these processes, microRNAs have emerged as crucial regulators of gene expression able to control the development and remodeling of neural connections. However, there is still a very limited understanding of their role in axon biology and inter-neuronal communication. Our central hypothesis is that specific miRNAs can be transported to the axon and regulate the development and function of neuronal connectivity via the control of local axonal translation (cis-action) and inter-neuronal (trans-action) mechanisms mediated by release of extracellular vesicles/exosomes. We will test this using a multidisciplinary approach with innovative cellular and molecular techniques based around compartmentalised microfluidic devices for the culture of mouse primary cortical neurons. The characterisation of axonal miRNAs and their capacity for intra- and inter- cellular action could transform our current understanding of the role of miRNAs in the development and function of neuronal networks. The impact of these findings will be many, both at the level of basic neuron connectivity, and in the understanding of neurodegenerative disease, where disruption of axonal projections and neuronal circuits has been intrinsically linked to progressive functional decline.