La régulation et la fonction des protéines Argonaute dans les dendrites des neurones hippocampiques
The processes controlling the translation of messenger RNAs into proteins play a critical role in the morphogenesis of neurons and in the plasticity of their synapses. The localization of certain messenger RNAs and their translation in dendrites are orchestrated by a particularly sophisticated regulation which is adapted to the compartmentalized morphology and excitable nature of neurons. MicroRNAs appear to be key players in the regulation of mRNA translation and protein expression at synapses. MicroRNAs are short, non-coding RNAs that specifically target messenger RNAs and regulate their translation into proteins. The microRNA pathway is controlled by a molecular machinery at the center of which are Argonaute proteins (AGO). However, the mechanisms regulating AGO proteins in neurons remain largely unknown. Ago2, the best characterized AGO protein in mammalian organisms, undergoes various modifications regulating, among other things, its localization, its stability, and its interaction with RNA. Such regulation and its physiological impact have not yet been described in neurons of the central nervous system. Thus, in my first study, we analyzed the regulation of Ago2 phosphorylation and stability by NMDA receptors, which play a central role in synaptic transmission and plasticity in neurons from the hippocampus, an important brain region for memory formation. We found that upon activation of NMDA receptors, Ago2 is dephosphorylated and degraded. Moreover, we observed that this regulation modulates the growth and maturation of spines found on dendrites and that represent synaptic sites. Apart from Ago2, the other predominant form of AGO protein in the brain is Ago1. However, the regulation and function of Ago1 in neurons remains obscure. Therefore, in my second study, we focused on comparing the regulation and function of Ago1 and Ago2 proteins on neuronal development. We found that expression of Ago1 protein decreases during neuronal development, whereas Ago2 protein levels appear to be more stable. Moreover, by manipulating the expression rate for each of these two proteins, we demonstrated a repressive influence of Ago1 and a permissive influence of Ago2 on the development of dendrites. By shedding light on how Ago1 and Ago2 function in hippocampal neurons, the results presented in this thesis define novel mechanisms regulating cellular adaptations necessary for neuronal homeostasis and structural plasticity of dendrites. In a wider scope, the work accomplished in the context of this research project contributes to elucidate the molecular processes underlying the development of cognitive functions.
dendrite phosphorylation Argonaute (AGO) protein; degradation messenger  RNA  (mRNA) microRNA (miRNA) neuron NMDA receptor phosphorylation spine translation