Systematic investigation of microRNA function in developing neurons

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Normal brain function critically depends on the integrity of biological networks that regulate the expression of genes. Discovered recently from studies in worms, microRNAs constitute a novel class of key regulators of gene expression regulation at the posttranscriptional level in the cell. Studies in animal models lacking all microRNAs have shown that they are essential for life as well as proper brain development. At this moment, fundamental questions such as how microRNAs interact and how they are globally implicated in neurobiology remain unanswered. Furthermore, the number and identity of microRNAs (and genes they regulate) implicated in neuronal development, particularly in a mammalian system, are unknown. In the current project we want to make use of the very well defined primary hippocampal neuron system to address these questions. As almost all the cells in culture follow in a synchronized way the different differentiation steps as seen in brain, from a neuronal round precursor cell towards fully polarized neurons with clear axon and dendritic subdomains and synaptic activity, it is possible to follow in a quantitative and qualitative way gradual changes in gene expression. We propose to investigate the role of microRNAs, first at a global level and then individually, in modulating the neuronal phenotype. These experiments will allow a first systematic investigation of how microRNAs contribute to the complexity of the neuronal network.