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Axonuclear Communication in Neuronal Growth Control

Final Report Summary - NEUROGROWTH (Axonuclear Communication in Neuronal Growth Control)

Cell size homeostasis is one of the most fundamental aspects of biology, with distinct
size ranges for individual cell types. Neurons are the largest known cells, with complex and
highly polarized morphologies. Moreover, axonal lengths impose a significant delay between
transcription and biosynthesis in the cell body and delivery of the components necessary for
growth and maintenance to the axon. The large dimensions of a growing neuron require active
transport by molecular motors for transfer of signals between neurites and cell body. In this
project, we showed that motor-dependent messenger RNA (mRNA) localization regulates
neuronal growth and cycling cell size. We identified the RNA-binding protein nucleolin as an
essential factor in importin beta1 mRNA transport to neuronal axons and to the cellular
periphery in fibroblasts. We showed that depletion of importin beta1 from axons by a 3’ UTR
knockout (KO) or by sequestration of nucleolin enhances neuronal outgrowth, concomitantly
with a subcellular shift in protein synthesis. Similar perturbations affect the morphology and
size of fibroblasts in culture (Perry et al. 2016). Thus, the subcellular localization of nucleolinassociated
mRNAs regulates axon length and cell size and growth control mechanisms.
The link between subcellular localization of protein synthesis and neuronal length sensing
motivated us to examine how protein synthesis is initiated locally in neurons. We found that
mTOR (mechanistic target of rapamycin), a central regulator of protein synthesis, was upregulated
and activated in injured axons, due to local translation of mTOR mRNA. This mRNA
was transported into axons by the cell size–regulating RNA-binding protein nucleolin.
Furthermore, mTOR controlled its own local translation and that of retrograde injury signaling
molecules such as importin beta1 and STAT3 (signal transducer and activator of transcription
3) in injured axons. Deletion of the mTOR 3′ untranslated region (3′UTR) in mice reduced
mTOR in axons and decreased local translation after nerve injury and decreased proprioceptive
neuronal survival after nerve injury. Thus, mRNA localization enables spatiotemporal control
of mTOR pathways regulating local translation and long-range intracellular signaling
(Terenzio et al., 2018).
Perry et al., 2016, Nucleolin-Mediated RNA Localization Regulates Neuron Growth and
Cycling Cell Size. Cell Reports 16, 1664–1676.
Terenzio et al., 2018, Locally translated mTOR controls axonal local translation in nerve
injury. Science 359, 1416–1421.
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