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

Abstract

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...

A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

“…Demonstrating the significance of these transcriptional changes, kdm5 A512P and kdm5 JmjC* mutant head, but not thorax, tissue showed attenuated translation. Short-term memory formation relies on the modification of existing proteins, whereas long-term memory is dependent on de novo protein synthesis to stabilize synaptic changes within the brain (Gal-Ben-Ari et al, 2012; Jung et al, 2012; Slomnicki et al, 2016). Thus, defective translation could contribute to the long-term learning and/or memory defects observed in our mutants either alone or in combination with the dysregulation of other genes involved in neuronal function.…”

Nucleolar Enrichment of Brain Proteins with Critical Roles in Human Neurodevelopment

“…Therefore, LARP7 and EMG1 may regulate different aspects of the complex process of ribosomal biogenesis. However, interference with either activity could result in similar ribosomal deficits as shown in rat hippocampal neurons whose ribosomal biogenesis was perturbed at the levels of rRNA transcription or post-transcriptional assembly of the large-or small ribosomal subunit (61).…”

“…In addition, neuronal maturation is associated with intense neurite outgrowth that involves ribosomal biogenesis (10,61). In fact, on postnatal day 7, when the nucleolar fractions of the cerebral cortex were obtained, there is neuritic growth and maturation but little neurogenesis in that region of the rodent brain (64).…”

Non-random distribution of methyl-CpG sites and non-CpG methylation in the human rDNA promoter identified by next generation bisulfite sequencing

“…While transient reduction of ribosomal biogenesis may be beneficial by improving cell survival under stress, its prolonged disruption may negatively affect translation-intensive processes such as proliferative cell growth or neuronal morphogenesis (Murayama et al 2008, Freed et al 2010, Slomnicki et al 2016). Although rate of ribosomal biogenesis declines as neurons become terminally post-mitotic, they keep expanding their ribosome content (Slomnicki et al 2016).…”