3′UTR-mediated translational control is proposed as an evolutionarily conserved mechanism for the maintenance of cell-type-specific proteostasis for the maintenance of cell-type-specific protein synthesis in neurons.
Abstract
The precise regulation of protein synthesis is essential for cellular function and survival. In particular, in neurons, dysregulated mRNA translation is linked to impaired memory formation and is a hallmark of neurodegenerative diseases. Neurons are characterized by tissue-specific, long 3′ untranslated regions (3′UTRs); in this study, we demonstrate that mRNA isoforms with these neuronal 3′UTRs are less efficiently translated than their short counterparts in Drosophila and mammalian brains. 3′UTR-dependent translation is based on a negative feedback mechanism centered around the two neural-enriched proteins ELAV and Pumilio. The long elav 3′UTR inhibits production of the neuronal ELAV protein, which in turn mediates 3′UTR extension of hundreds of neuronal genes. Those long 3′UTR isoforms are preferentially bound and translationally inhibited by Pumilio. The regulatory loop maintains optimal neuronal 3′UTR and protein levels in conditions of genetic and environmental perturbations; its disruption reduces animal viability and lowers stress resilience, and causes severe developmental phenotypes in flies and in human brain organoids. We propose 3′UTR-mediated translational control as an evolutionarily conserved mechanism for the maintenance of cell-type-specific proteostasis.
Nonsense-mediated mRNA decay (NMD) is a basic post-transcriptional mechanism ensuring the fidelity of many biological processes including brain development. Together with alternative splicing, it regulates the inclusion of poison exons. NMD is involved in the control of multiple processes during brain development such as neural progenitor proliferation and differentiation, neuronal migration, axonal guidance, and synaptic plasticity. Under physiological conditions, this mechanism safeguards neuronal identity and the functional maturation of the brain. When disrupted, the consequences range from structural cerebral anomalies to cognitive impairment and epilepsy. This review examines NMD-mediated regulatory mechanisms across different stages of brain development. Special emphasis is placed on how dysfunction in NMD pathway components—specifically core degradation factors, the exon junction complex, and neuron-specific splicing regulators—underpins an extensive array of neurodevelopmental disorders (NDDs). Furthermore, we delineate the relationship between the position of a premature termination codon (PTC) within a transcript and the resulting molecular outcome. While the degradation of aberrant mRNAs often leads to haploinsufficiency, their escape from NMD might result in the accumulation of truncated proteins with dominant-negative effects, thereby causing specific clinical phenotypes in affected patients. Elucidating these mechanisms is essential for both the interpretation of variant pathogenicity and the development of targeted therapeutic strategies.
Polina E Anisimova, A. Filat'eva, Victor S Tarabykin et al.· Frontiers in Molecular Biosc...· 0 citations
The molecular regulatory networks of CELF4 and its mechanisms across multisystem diseases are reviewed, the current status and limitations of clinical translation are discussed, and future research on diagnostic biomarkers and therapeutic strategies targeting this protein is guided.
Qingsong Wang, Wenlong Yue, D. Lin et al.· Frontiers in Molecular Biosc...· 0 citations
Longevity and stress resilience require precise coordination of gene expression programs across tissues. Here, we demonstrate that overexpression of the chromatin reader bet-1 specifically in neurons of Caenorhabditis elegans promotes organismal longevity and stress resistance via cell-nonautonomous signaling. Neuronal bet-1 elicits a neurotransmitter-dependent signal that activates the conserved stress-responsive transcription factor HSF-1 in the intestine, enhancing proteostasis, oxidative stress resistance, metabolic remodeling, and immune defense. Life span extension by neuronal bet-1 requires both hsf-1 and daf-16 in neurons but only requires hsf-1 in peripheral tissues. Using bulk RNA sequencing, we reveal distinct prolongevity pathways that include enhanced heat-shock response, proteostasis, increased actin stability, and resistance to pathogens, which likely together coordinate the prolongevity effects of neuronal bet-1 Our findings establish BET-1 as a potent nonautonomous regulator of aging and stress response, highlighting chromatin readers as upstream modulators of intertissue signaling and systemic resilience.
Naibedya Dutta, Daniel Hicks, Edgar Esparza et al.· Genes & Development· 0 citations
A ribosome tagging and purification strategy is developed that bypasses the prolonged turnover of ribosomal proteins, enabling ribosome profiling with one-hour temporal resolution after neural stimulation, and uncovered previously unknown activity-dependent alternative translation with functional implication, such as the uORF of Egr1.
Nayan Suryawanshi, Hitoshi Uchida, R. Endo et al.· Nature Communications· 0 citations
Proper nervous system development is critical for brain function, and deficits in neural development are implicated in many brain disorders. Neurons are distinctly polarized cells where mRNA can be transported to distal structures like axons and dendrites. Recent discoveries of widespread mRNA chemical modifications raise the question of their post-transcriptional regulatory role in brain development and function. N6-methyladenosine (m6A), installed by the METTL3/METTL14 methyltransferase complex, is the most prevalent internal mRNA modification, influencing stability, translation, splicing, and localization. However, the impact of m6A modification on RNA transport in developing neurons is not well understood. In this study, we find that the ablation of Mettl14 in postmitotic neurons leads to impaired axonal projection during corticogenesis. RNA-seq and single-molecule in situ hybridization reveal mislocalization of mRNAs in neurites of neurons with m6A loss-of-function. Furthermore, m6A-SAC-seq to identify a single nucleotide resolution m6A maps in the perinatal brain uncovers m6A-tagged transcripts associated with synapse organization, mRNA processing, and axonogenesis. We also identify YTHDF2 as the reader protein responsible for mRNA transport in callosal projection axons. YTHDF2 interacts with motor proteins, translational regulators, and microtubules to facilitate distal transport of m6A-tagged mRNA. Our data suggest that FMRP may serve as a context-guiding interactor that reshapes the YTHDF2 complex by recruiting specific cofactors and motor proteins, thereby promoting transport rather than degradation of m⁶A-tagged transcripts. Together, these findings provide insight into the epitranscriptomic mechanisms governing axon projection and guidance during mammalian cortical neurogenesis. Precise mRNA transport into neurites is essential for neural circuit formation. Here, the authors show that m6A RNA marks recruit YTHDF2-associated transport machinery that favors transport over degradation, localizing selected mRNAs to neurites to promote cortical axon projection.
Bonsang Koo, Ajeet Kumar, H. Hwang et al.· Nature Communications· 0 citations
The potential role of ribonucleoprotein-based transport as a primary mechanism driving circRNA localization is explored and how such spatial distribution influences synaptic plasticity and post-transcriptional gene regulation is examined.
Nicolò Salvi, M. Morlando· Non-Coding RNA· 0 citations