Membrane-less organelles, because of their capacity to dynamically, selectively and reversibly concentrate molecules, are very well adapted for local information processing and rapid response to environmental fluctuations. These features are particularly important in the context of neuronal cells, where synapse-specific activation, or localized extracellular cues, induce signaling events restricted to specialized axonal or dendritic subcompartments. Neuronal ribonucleoprotein (RNP) particles, or granules, are nonmembrane bound macromolecular condensates that concentrate specific sets of mRNAs and regulatory proteins, promoting their long-distance transport to axons or dendrites. Neuronal RNP granules also have a dual function in regulating the translation of associated mRNAs: while preventing mRNA translation at rest, they fuel local protein synthesis upon activation. As revealed by recent work, rapid and reversible switches between these two functional modes are triggered by modifications of the networks of interactions underlying RNP granule assembly. Such flexible properties also come with a cost, as neuronal RNP granules are prone to transition into pathological aggregates in response to mutations, aging, or cellular stresses, further emphasizing the need to better understand the mechanistic principles governing their dynamic assembly and regulation in living systems. K E Y W O R D S biological condensates, local translation, neuronal compartments, neuronal RNA granule, RNP complex 1 | INTRODUCTION Neurons are highly polarized cells specialized in complex information processing, transfer and local storage. They are compartmentalized into macroscopic functional domains-the dendrites, soma and axons-themselves further divided into operational subcompartments locally integrating external signals. 1 These subcompartments are not defined by structural boundaries, but rather by their enrichment in specialized supramolecular complexes. Axon growth cones, for example, are enriched in signaling molecules, components of the protein synthesis and degradation machineries, and cytoskeletal regulators, that together promote physical turning or collapse in response to chemical or mechanical guidance cues. 2,3 Dendritic spines are enriched in postsynaptic proteins such as transmembrane receptors, channels and downstream signal transduction components modulating synaptic strength in response to neuronal activation or inhibition. 4-7Remarkably, neuronal subcompartments are highly plastic and undergo extensive remodeling of their proteomes in response to external cues. 8,9 Such a remodeling involves local protein synthesis of new proteins, a process achieved via the translation activation of localized mRNAs transported from the soma in a translationally silent Nadia Formicola and Jeshlee Vijayakuma contributed equally to this study.
Prion-like domains (PLDs), defined by their low sequence complexity and intrinsic disorder, are present in hundreds of human proteins. Although gain-of-function mutations in the PLDs of neuronal RNA-binding proteins have been linked to neurodegenerative disease progression, the physiological role of PLDs and their range of molecular functions are still largely unknown. Here, we show that the PLD of Drosophila Imp, a conserved component of neuronal ribonucleoprotein (RNP) granules, is essential for the developmentally-controlled localization of Imp RNP granules to axons and regulates in vivo axonal remodeling. Furthermore, we demonstrate that Imp PLD restricts, rather than promotes, granule assembly, revealing a novel modulatory function for PLDs in RNP granule homeostasis. Swapping the position of Imp PLD compromises RNP granule dynamic assembly but not transport, suggesting that these two functions are uncoupled. Together, our study uncovers a physiological function for PLDs in the spatio-temporal control of neuronal RNP assemblies.
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