Neurons are the largest known cells, with complex and highly polarized morphologies. As such, neuronal signaling is highly compartmentalized, requiring sophisticated transfer mechanisms to convey and ...integrate information within and between sub-neuronal compartments. Here, we survey different modes of compartmentalized signaling in neurons, highlighting examples wherein the fundamental cell biological processes of protein synthesis and degradation, membrane trafficking, and organelle transport are employed to enable the encoding and integration of information, locally and globally within a neuron. Comparisons to other cell types indicate that neurons accentuate widely shared mechanisms, providing invaluable models for the compartmentalization and transfer mechanisms required and used by most eukaryotic cells.
Terenzio et al. survey the influence of neuronal size and polarization on compartmentalized signaling, highlighting roles for protein synthesis and degradation, membrane trafficking, and organelle transport. Neuronal mechanisms provide invaluable models for studying the cell biology of signaling in diverse cell types.
How is protein synthesis initiated locally in neurons? We found that mTOR (mechanistic target of rapamycin) was activated and then up-regulated in injured axons, owing to local translation of mTOR ...messenger RNA (mRNA). This mRNA was transported into axons by the cell size-regulating RNA-binding protein nucleolin. Furthermore, mTOR controlled local translation in injured axons. This included regulation of its own translation and that of retrograde injury signaling molecules such as importin β1 and STAT3 (signal transducer and activator of transcription 3). Deletion of the mTOR 3' untranslated region (3'UTR) in mice reduced mTOR in axons and decreased local translation after nerve injury. Both pharmacological inhibition of mTOR in axons and deletion of the mTOR 3'UTR decreased proprioceptive neuronal survival after nerve injury. Thus, mRNA localization enables spatiotemporal control of mTOR pathways regulating local translation and long-range intracellular signaling.
•Local translation contributes to retrograde injury signaling and axon regeneration.•Numerous mRNAs localize to axons in different neuron types.•Diverse sources have been proposed for axonal ...ribosomes.•mTOR and other kinases drive local translation in axons.
Neurons convey signals over long distances, for example motor neurons and sensory neurons project axons up to a meter long in humans. To this end, a sophisticated network of long-range signaling mechanisms enables communication between neuronal processes and somata. These mechanisms are activated during axonal injury and have essential roles both for sensing the injury and regulating subsequent regeneration. Here we survey the role of one such mechanism, axonal translation, which contributes to both retrograde injury signaling and as a source of proteins for regenerating axons. The nature of the axonal synthesis machinery has become progressively clearer over the past decade. A large number of axonally localized mRNAs have been identified, which cover a wide spectrum of protein families; and axonal ribosomes have been detected, even though their origin is still subject to debate. Various kinase pathways, most prominently mTOR, have been implicated in driving local translation in axons. Finally, new technologies are becoming available to visualize axonal translation and enable proteomic analyses. These technological improvements offer new avenues towards comprehensive characterization of the axonal translational machinery.
Neurons grow during development and extend long axons to make contact with their targets with the help of an intrinsic program of axonal growth as well as a range of extrinsic cues and a permissive ...milieu. Injury events in adulthood induce some neuron types to revert to a regenerative state in the peripheral nervous system (PNS). Neurons from the central nervous system (CNS), however, reveal a much lower capacity for regenerative growth. A number of intrinsic regeneration-promoting mechanisms have been described, including priming by calcium waves, epigenetic modifications, local mRNA translation, and dynein-driven retrograde transport of transcription factors (TFs) or signaling complexes that lead to TF activation and nuclear translocation. Differences in the availability or recruitment of these mechanisms may partially explain the limited response of CNS neurons to injury.
Individual cell types have characteristic sizes, suggesting that size sensing mechanisms may coordinate transcription, translation, and metabolism with cell growth rates. Two types of size-sensing ...mechanisms have been proposed: spatial sensing of the location or dimensions of a signal, subcellular structure or organelle; or titration-based sensing of the intracellular concentrations of key regulators. Here we propose that size sensing in animal cells combines both titration and spatial sensing elements in a dynamic mechanism whereby microtubule motor-dependent localization of RNA encoding importin β1 and mTOR, coupled with regulated local protein synthesis, enable cytoskeleton length sensing for cell growth regulation.
Injury to axons elicits changes in macromolecule synthesis in the corresponding cell bodies that are critical for an effective regenerative response. For decades the most easily studied aspect of ...this phenomenon was the onset of chromatolysis, a suite of structural changes in the cell body characterized by swelling, shifting of the nucleus and dispersal of Nissl bodies. The question: ‘what is the signal for chromatolysis?’ received no less than 10 possible answers in a comprehensive review article published more than three decades ago. Here we come back to this 36 years old question, and review progress on understanding the mechanism of retrograde injury signaling in lesioned peripheral nerves. Recent work suggests that this is based on local axonal synthesis of critical carrier proteins, including importins and vimentin that link diverse signaling molecules to the dynein retrograde motor. A multiplicity of binding sites and of potential signaling molecules, including transcription factors and MAP kinases (Erk, Jnk), may allow diverse options for information‐rich encoding of the injury status of the axon for transmission to the cell body.
The GTPase Ran is best known for its crucial roles in the regulation of nucleocytoplasmic transport in interphase cells and in the organization of the spindle apparatus during mitosis. A flurry of ...recent reports has now implicated Ran in diverse cytoplasmic events, including trafficking of an ephrin receptor homolog in nematode oocytes, control of neurite outgrowth in Drosophila and mammalian neurons, and retrograde signaling in nerve axons after injury. Striking findings suggest that the guanine-nucleotide state of Ran can be regulated by local translation of the Ran-binding protein RanBP1 in axons, and that an additional Ran-binding protein, RanBP10, can act as a microtubule-binding cytoplasmic guanine-nucleotide exchange factor for Ran (RanGEF) in megakaryocytes. Thus, the Ran GTPase system can act as a spatial regulator of importin-dependent transport and signaling in distal cytoplasm, and as a regulator of cytoskeletal dynamics at sites that are distant from the nucleus.
The cytoplasmic dynein motor complex transports essential signals and organelles from the cell periphery to the perinuclear region, hence is critical for the survival and function of highly polarized ...cells such as neurons. Dynein Light Chain Roadblock-Type 1 (DYNLRB1) is thought to be an accessory subunit required for specific cargos, but here we show that it is essential for general dynein-mediated transport and sensory neuron survival. Homozygous Dynlrb1 null mice are not viable and die during early embryonic development. Furthermore, heterozygous or adult knockdown animals display reduced neuronal growth, and selective depletion of Dynlrb1 in proprioceptive neurons compromises their survival. Conditional depletion of Dynlrb1 in sensory neurons causes deficits in several signaling pathways, including β-catenin subcellular localization, and a severe impairment in the axonal transport of both lysosomes and retrograde signaling endosomes. Hence, DYNLRB1 is an essential component of the dynein complex, and given dynein's critical functions in neuronal physiology, DYNLRB1 could have a prominent role in the etiology of human neurodegenerative diseases.
•Depletion of DYNLRB1 impairs neurite outgrowth in sensory neurons.•Complete knockout of DYNLRB1 causes early embryonic lethality.•Specific repression of DYNLRB1 causes loss of proprioceptive neurons and impairs proprioception.•DYNLRB1 is required for effective axonal retrograde transport of lysosomes and signaling endosomes.
Critical functions of intra-axonally synthesized proteins are thought to depend on regulated recruitment of mRNA from storage depots in axons. Here we show that axotomy of mammalian neurons induces ...translation of stored axonal mRNAs via regulation of the stress granule protein G3BP1, to support regeneration of peripheral nerves. G3BP1 aggregates within peripheral nerve axons in stress granule-like structures that decrease during regeneration, with a commensurate increase in phosphorylated G3BP1. Colocalization of G3BP1 with axonal mRNAs is also correlated with the growth state of the neuron. Disrupting G3BP functions by overexpressing a dominant-negative protein activates intra-axonal mRNA translation, increases axon growth in cultured neurons, disassembles axonal stress granule-like structures, and accelerates rat nerve regeneration in vivo.
PDF
