Neuronal RNA Granules: Movers and Makers

Kiebler, Michael; Bassell, Gary J.

doi:10.1016/j.neuron.2006.08.021

Cited by 513 publications

(510 citation statements)

References 34 publications

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“…In either case, inhibiting CPEB1-mediated mRNA translation, with the use of DN-CPEB1-GFP, clearly inhibits tumor growth. Increasingly, roles for localized mRNA translation in specific cellular compartments are being established and the molecular mechanisms regulating mRNA trafficking and translation are now being elucidated (36,37). One wellstudied example of an element in the 3 0 -UTR being responsible for cellular trafficking is the b-actin zipcode.…”

Section: Discussionmentioning

confidence: 99%

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Kochanek

Wells

2013

Molecular Cancer Research

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Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is an mRNA-binding protein present in both neurons and glia. CPEB1 is capable of both repressing mRNA translation and activating it depending upon its phosphorylation state. CPEB1-bound mRNAs are held in translational dormancy until CPEB1 is phosphorylated, leading to the cytoplasmic polyadenylation of the bound mRNA that triggers translation. Here, we show that CPEB1 can bind to and regulate translation of the mRNA-encoding metadherin (MTDH, also known as AEG-1 and Lyric) in the rat glioblastoma cell line CNS1. MTDH/AEG-1 is being revealed as a critical signaling molecule in tumor progression, playing roles in invasion, metastasis, and chemoresistance. By using a mutant of CPEB1 that cannot be phosphorylated (thereby holding target mRNAs in translational arrest), we show that inhibiting CPEB1-mediated translation blocks MTDH/AEG-1 expression in vitro and inhibits glioblastomas tumor growth in vivo. CPEB1-mediated translation is likely to impact several signaling pathways that may promote tumor progression, but we present evidence suggesting a role in directed cell migration in glioblastoma cells. In addition, reporter mRNA containing CPEB1-binding sites is transported to the leading edge of migrating cells and translated, whereas the same mRNA with point mutations in the binding sites is synthesized perinuclearly. Our findings show that CPEB1 is hyperactive in rat glioblastoma cells and is regulating an important cohort of mRNAs whose increased translation is fueling the progression of tumor proliferation and dispersal in the brain. Thus, targeting CPEB1-mediated mRNA translation might be a sound therapeutic approach. Mol Cancer Res; 11(2); 149-60. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Kochanek

Wells

2013

Molecular Cancer Research

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“…Despite the absence of translating mRNPs, many neuronal granules also harbor ribosomes. 5 P-bodies, which are generally seen in all cell types, are defined by enrichment for mRNA decay proteins, 1 whereas stress granules normally only form during cellular stress, and contain numerous initiation factors, including small ribosomal subunits. 3 Both types are thought to contribute to regulation of translation, whereas P-bodies are also thought to function in mRNA decay.…”

Section: Diversity and Similarity Among Different Mrnp Granule Typesmentioning

confidence: 99%

“…In eukaryotes, nontranslating mRNPs often assemble together into visible cytoplasmic structures that lack a limiting membrane, termed mRNP granules. Specific examples of these include P-bodies, 1,2 stress granules, 2,3 germ granules, 4 and neuronal transport granules 5 (Fig. 1).…”

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confidence: 99%

mRNP granules

2014

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“…Among these structures, stem-loop III (nucleotides 213-238) manifested ∼73% sequence homology across three mammalian species. Interestingly, cis-acting localizing elements have been shown to often form stemloop structures recognized by RNA binding proteins (Bassell and Singer 1997;Kiebler and Bassell 2006). Based on these observations, it was hypothesized that the 3 ′ UTR of TH contained elements that mediated the localization of TH mRNA to distal axons and presynaptic terminals.…”

Section: Local Synthesis Of Th Facilitates Axonal Dopamine Productionmentioning

confidence: 99%

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

Gervasi

Scott

Aschrafi

et al. 2016

RNA

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Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3 ′ UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal.

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Neuronal RNA Granules: Movers and Makers

Cited by 513 publications

References 34 publications

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

mRNP granules

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

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