The prion-like domain of Drosophila Imp promotes axonal transport of RNP granules in vivo

Vijayakumar, Jeshlee; Perrois, Charlène; Heim, M; Bousset, Luc; Alberti, Simon; Besse, Florence

doi:10.1038/s41467-019-10554-w

Cited by 31 publications

(29 citation statements)

References 68 publications

(107 reference statements)

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“…This suggests that oskar granules in Hrp48-depleted/truncated lines have altered physical properties that impair their native function, and imply a role of the Hrp48-PrLD in modulating granule material properties. Similar observation has been made in case of Imp, a conserved component of Drosophila neuronal RNP granules (Vijayakumar et al, 2019). Biomolecular condensates exhibit a continuum of material and emergent properties that can be harnessed by the cell to specific needs (Alberti, 2017).…”

Section: Resultssupporting

confidence: 86%

Liquid-to-solid phase transition ofoskarRNP granules is essential for their function in theDrosophilagermline

Bose

Mahamid²,

Ephrussi

2021

Preprint

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Asymmetric localization of oskar RNP granules to the oocyte posterior is crucial for abdominal patterning and germline formation of the Drosophila embryo. We show that oskar RNP granules in the oocyte are condensates with solid-like physical properties. Using purified oskar RNA and scaffold proteins Bruno and Hrp48, we confirm in vitro that oskar granules undergo a liquid-to-solid phase transition. Whereas the liquid phase allows RNA incorporation, the solid phase precludes incorporation of additional RNA while allowing RNA-dependent partitioning of specific proteins. Genetic modification of scaffold granule proteins, or tethering the intrinsically disordered region of human Fused in Sarcoma to oskar mRNA, allowed modulation of granule material properties in vivo. The resulting liquid-like properties impaired oskar localization and translation with severe consequences on embryonic development. Our study reflects how physiological phase transitions shape RNA-protein condensates to regulate localization and expression of a maternal RNA that instructs germline formation.

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Section: Resultssupporting

confidence: 86%

Liquid-to-solid phase transition ofoskarRNP granules is essential for their function in theDrosophilagermline

Bose

Mahamid²,

Ephrussi

2021

Preprint

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“…Further characteristic of a liquid state, neuronal granules are subject to rapid internal rearrangements, as visualized in fluorescence recovery after photobleaching (FRAP) experiments after half‐bleaching of granules. Intra‐granule diffusion of molecules is also associated with exchange of molecules with the surrounding cytoplasmic environment, typically on the time‐scales of seconds to minutes, although turnover rates appear to depend on granule type and/or component …”

Section: Neuronal Rnp Granules Are Dynamic Membrane‐less Condensatesmentioning

confidence: 99%

“…As most of the prion‐like domains studied so far trigger phase separation in vitro, the prevalent view is that they may function as autonomous modules for RNP granule assembly . More recent work has, however, suggested that they may rather have chaperone‐like functions, behaving as modifiers of phase separation and granule material properties . Although such a protein‐centric way of considering RNP assembly fits with the fact that neuronal RNP granules have historically been defined based on their characteristic protein markers (eg, FMRP, ZBP1, Staufen 2, Barentsz, CPEB, TDP‐43), it does not take into account the contribution of a major player in the system: RNA.…”

Section: How and Where Are Neuronal Rnp Granule Assembled?mentioning

confidence: 99%

Neuronal ribonucleoprotein granules: Dynamic sensors of localized signals

Formicola

Vijayakumar

Besse

2019

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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.

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“…In vitro and ex vivo live-imaging of fluorescently-tagged mRNAs or their associated RBPs has revealed that RNP assemblies are transported to distal axons through active, bi-directional motion characterized by the presence of both anterograde and retrograde processive events interspaced by long stationary phases (Knowles et al, 1996; Tiruchinapalli et al, 2003; Leung et al, 2006, 2018; Nalavadi et al, 2012; Alami et al, 2014; Medioni et al, 2014; Gopal et al, 2017; Wong et al, 2017; De Graeve and Besse, 2018; Turner-Bridger et al, 2018; Vijayakumar et al, 2019). Long-range transport of RNP granules along the axon shaft relies on the integrity of the microtubule cytoskeleton (Knowles et al, 1996; Medioni et al, 2014; Leung et al, 2018) and likely requires the combined activity of kinesin and dynein motors, although direct evidence is still scarce (Das et al, 2019).…”

Section: Membrane-bound Organelles As Vehicles For Axonal Transport Omentioning

confidence: 99%

Local Translation in Axons: When Membraneless RNP Granules Meet Membrane-Bound Organelles

Pushpalatha

Besse

2019

Front. Mol. Biosci.

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Eukaryotic cell compartmentalization relies on long-known membrane-delimited organelles, as well as on more recently discovered membraneless macromolecular condensates. How these two types of organelles interact to regulate cellular functions is still largely unclear. In this review, we highlight how membraneless ribonucleoprotein (RNP) organelles, enriched in RNAs and associated regulatory proteins, cooperate with membrane-bound organelles for tight spatio-temporal control of gene expression in the axons of neuronal cells. Specifically, we present recent evidence that motile membrane-bound organelles are used as vehicles by RNP cargoes, promoting the long-range transport of mRNA molecules to distal axons. As demonstrated by recent work, membrane-bound organelles also promote local protein synthesis, by serving as platforms for the local translation of mRNAs recruited to their outer surface. Furthermore, dynamic and specific association between RNP cargoes and membrane-bound organelles is mediated by bi-partite adapter molecules that interact with both types of organelles selectively, in a regulated-manner. Maintaining such a dynamic interplay is critical, as alterations in this process are linked to neurodegenerative diseases. Together, emerging studies thus point to the coordination of membrane-bound and membraneless organelles as an organizing principle underlying local cellular responses.

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The prion-like domain of Drosophila Imp promotes axonal transport of RNP granules in vivo

Cited by 31 publications

References 68 publications

Liquid-to-solid phase transition ofoskarRNP granules is essential for their function in theDrosophilagermline

Liquid-to-solid phase transition ofoskarRNP granules is essential for their function in theDrosophilagermline

Neuronal ribonucleoprotein granules: Dynamic sensors of localized signals

Local Translation in Axons: When Membraneless RNP Granules Meet Membrane-Bound Organelles

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