RNA Polymerase 1-driven Transcription as a Mediator of BDNF-induced Neurite Outgrowth

Gomes, Cynthia; Smith, Stacy L.; Youssef, Mark N.; Zheng, Jing; Hagg, Theo; Hetman, Michał

doi:10.1074/jbc.m110.170134

Cited by 51 publications

(67 citation statements)

References 47 publications

(59 reference statements)

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“…Such a response has been associated with nucleolar disruption and activation of p53. In addition, we have previously reported that pol 1 is necessary for neurite outgrowth in response to activation of the BDNF-ERK1/2 signaling cascade (22). Although such observations may suggest that ribosome biogenesis is critical for neuronal morphogenesis, they do not prove its role in this process.…”

mentioning

confidence: 69%

“…One can speculate that the appearance of such pro-axonal effects of BDNF may be related to enhanced activation of growth-promoting signaling pathways and/or greater neuronal responsiveness to such activations. Despite strong effects on dendritic development (22), shTIF1A had no significant effects on axonal length with or without BDNF (Fig. 10, F and G).…”

Section: Inhibition Of Ribosome Production Impairs Bdnf-induced Enhanmentioning

confidence: 99%

“…Plasmids-The following plasmids were described previously: chicken ␤-actin promoter-driven EGFP (26) and RFP (27); tagged ribosomal protein vectors RPS6-EGFP, RPS14-Venus, and RPL4-EGFP (28); CRE-luciferase and EF1␣-LacZ (EF1␣ promoter-driven ␤-galactosidase) (29); Kif5C560-dTomato (30); shTIF1A, shGFP, and DN-p53 (19); shLuc (22); and pSuper-TRE and ptTS (31).…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, disruption of proliferative growth following inactivation of a pol 1 co-factor Treacle has been shown to be a consequence of p53 activation rather than ribosomal depletion (23). Although the pol 1 requirement for neurite outgrowth was demonstrated with p53 being blocked to enhance survival of pol 1-inhibited neurons, it is conceivable that disruption of the p53-independent, nonribosomal functions of the nucleolus may reduce morphogenesis (22). Examples of such functions include negative regulation of some branches of stress signaling or non-rRNA processing (24,25).…”

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confidence: 99%

See 3 more Smart Citations

Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree

Słomnicki

Pietrzak

Vashishta

et al. 2016

Journal of Biological Chemistry

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The nucleolus serves as a principal site of ribosome biogenesis but is also implicated in various non-ribosomal functions, including negative regulation of the pro-apoptotic transcription factor p53. Although disruption of the nucleolus may trigger the p53-dependent neuronal death, neurotoxic consequences of a selective impairment of ribosome production are unclear. Here, we report that in rat forebrain neuronal maturation is associated with a remarkable expansion of ribosomes despite postnatal down-regulation of ribosomal biogenesis. In cultured rat hippocampal neurons, inhibition of the latter process by knockdowns of ribosomal proteins S6, S14, or L4 reduced ribosome content without disrupting nucleolar integrity, cell survival, and signaling responses to the neurotrophin brain-derived neurotrophic factor. Moreover, reduced general protein synthesis and/or formation of RNA stress granules suggested diminished ribosome recruitment to at least some mRNAs. Such a translational insufficiency was accompanied by impairment of brain-derived neurotrophic factor-mediated dendritic growth. Finally, RNA stress granules and smaller dendritic trees were also observed when ribosomal proteins were depleted from neurons with established dendrites. Thus, a robust ribosomal apparatus is required to carry out protein synthesis that supports dendritic growth and maintenance. Consequently, deficits of ribosomal biogenesis may disturb neurodevelopment by reducing neuronal connectivity. Finally, as stress granule formation and dendritic loss occur early in neurodegenerative diseases, disrupted homeostasis of ribosomes may initiate and/or amplify neurodegeneration-associated disconnection of neuronal circuitries.The ribosome is the principal component of the protein synthesis machinery. Most steps of ribosomal biogenesis occur in the nucleolus starting with the RNA-polymerase-1 (pol 1) 2 -mediated transcription of rRNA genes (1). In addition, pol 1 activity is required for the maintenance of the nucleolus. Therefore, inhibition of pol 1 not only blocks ribosomal biogenesis but also perturbs non-ribosomal functions of the nucleolus, including negative regulation of the pro-apoptotic transcription factor p53 (2). Although pol 1 initiates ribosome production, many additional steps are required for that process, including rRNA processing and binding to ribosomal proteins (RPs) (3). Consequently, depletion of various RPs, including S6 or S14, disrupts ribosomal biogenesis without interfering with nucleolar integrity (4). Impaired ribosome production and/or ribosomal deficits are documented in various neurodegenerative diseases, including Alzheimer, Huntington, Parkinson, amyotrophic lateral sclerosis (ALS), and fronto-temporal lobe dementia (FTLD) (5-13). Reduced ribosomal biogenesis may also contribute to neurodevelopmental disorders. Thus, microcephaly and neurodevelopmental delays are present in Bowen-Conradi syndrome that is caused by deficiency of the ribosomal biogenesis factor EMG1 or in patients with a newly described RPL10 ribos...

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mentioning

confidence: 69%

Section: Inhibition Of Ribosome Production Impairs Bdnf-induced Enhanmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree

Słomnicki

Pietrzak

Vashishta

et al. 2016

Journal of Biological Chemistry

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“…20 Uncoupled overexpression of bacterial rDNA results in increased free ribosomal subunits with marked dominant negative effect. 21 The effect of excessive rRNA on neural tissue could be deleterious and might even culminate in neurodegeneration; in adult rat hippocampal neurons, enhanced Pol I activation promoted neurite outgrowth, including abnormally increased total neurite length and branching, 22 which in itself was shown to precede neurodegeneration. 23 Cell mitosis and DNA damage repair could also be affected by excessive transcription of rDNA due to depletion of untranscribed rDNA.…”

mentioning

confidence: 99%

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Edvardson

Nicolae

Agrawal

et al. 2017

The American Journal of Human Genetics

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Brain‐derived neurotrophic factor‐induced regulation of RNA metabolism in neuronal development and synaptic plasticity

et al. 2022

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The neurotrophin brain‐derived neurotrophic factor (BDNF) plays multiple roles in the nervous system, including in neuronal development, in long‐term synaptic potentiation in different brain regions, and in neuronal survival. Alterations in these regulatory mechanisms account for several diseases of the nervous system. The synaptic effects of BDNF mediated by activation of tropomyosin receptor kinase B (TrkB) receptors are partly mediated by stimulation of local protein synthesis which is now considered a ubiquitous feature in both presynaptic and postsynaptic compartments of the neuron. The capacity to locally synthesize proteins is of great relevance at several neuronal developmental stages, including during neurite development, synapse formation, and stabilization. The available evidence shows that the effects of BDNF–TrkB signaling on local protein synthesis regulate the structure and function of the developing and mature synapses. While a large number of studies have illustrated a wide range of effects of BDNF on the postsynaptic proteome, a growing number of studies also point to presynaptic effects of the neurotrophin in the local regulation of the protein composition at the presynaptic level. Here, we will review the latest evidence on the role of BDNF in local protein synthesis, comparing the effects on the presynaptic and postsynaptic compartments. Additionally, we overview the relevance of BDNF‐associated local protein synthesis in neuronal development and synaptic plasticity, at the presynaptic and postsynaptic compartments, and their relevance in terms of disease. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA Export and Localization > RNA Localization

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RNA Polymerase 1-driven Transcription as a Mediator of BDNF-induced Neurite Outgrowth

Cited by 51 publications

References 47 publications

Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree

Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Brain‐derived neurotrophic factor‐induced regulation of RNA metabolism in neuronal development and synaptic plasticity

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