Nucleolin-Mediated RNA Localization Regulates Neuron Growth and Cycling Cell Size

Abstract

SummaryHow can cells sense their own size to coordinate biosynthesis and metabolism with their growth needs? We recently proposed a motor-dependent bidirectional transport mechanism for axon length and cell size sensing, but the nature of the motor-transported size signals remained elusive. Here, we show that motor-dependent mRNA localization regulates neuronal growth and cycling cell size. We found that the RNA-binding protein nucleolin is associated with importin β1 mRNA in axons. Perturbation of nucleolin association with kinesins reduces its levels in axons, with a concomitant reduction in axonal importin β1 mRNA and protein levels. Strikingly, subcellular sequestration of nucleolin or importin β1 enhances axonal growth and causes a subcellular shift in protein synthesis. Similar findings were obtained in fibroblasts. Thus, subcellular mRNA localization regulates size and growth in both neurons and cycling cells.

Mechanisms and consequences of subcellular RNA localization across diverse cell types

“…This model suggests that localization of mRNA to projections, local translation to produce protein, followed by retrograde protein diffusion back to the nucleus allows the cell to sense projection length. This mechanism has been suggested to regulate cilia, flagella 63, 64 and neurite length 65, 66 . However, it could be broadly applicable to other subcellular components such as organelle size.…”

hnRNPs Interacting with mRNA Localization Motifs Define AxoNAl RNA Regulons

“…This suggests additional cytoplasmic and axonal functions for these RBPs in post-mitotic neurons, perhaps due to the much greater expanses of cytoplasm that neurons must grow and sustain with their long axonal processes. Multifunctionality has been documented for several RBPs, including axonal ZBP1, FMRP, nucleolin, and HuD that contribute to transport and stability or transport and translation of neuronal mRNAs (6,(51)(52)(53)(54). Both the RIP-seq data and depletion studies point to functions in axonal growth for hnRNP H1, F, and K. It will be of high interest to determine the molecular mechanisms for growth promotion by these hnRNPs and distinguish nuclear and somatic vs. axonal functions for these proteins.…”

“…For example, zip-code binding protein 1 (ZBP1, also called IGF-II mRNA binding [IMP1]) protein was shown to bind to a 56 nucleotide (nt) stem-loop structure in the 3' untranslated region (UTR) of β-actin mRNA (Actb), and this binding is necessary for axonal transport of the mRNA (6,7). Other RBPs implicated in axonal mRNA transport include nucleolin (Ncl), HuD (also called ELAVL4), hnRNP Q, hnRNP R, splicing factor proline and glutamine-rich (SFPQ), fragile X mental retardation (FMRP), Hermes, TRF2-S, and TDP-43 proteins (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Despite increased insight into RNA transport and translation, including the identification of literally thousands of axonal mRNAs (18,19), relatively few RBPs have been identified in axons.…”

DYNLRB1 is Essential for Dynein Mediated Transport and Neuronal Survival

“…In previous work, we identified a role for the dynein complex in regulating axon growth rates [22,23]. A screen of all dynein accessory subunits now shows that knockdown of Dynlrb1 reduces neurite outgrowth in cultured sensory neurons.…”