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.
Abstract
Circular RNAs (circRNAs) have recently emerged as a class of abundant and remarkably stable non-coding RNAs preferentially enriched in the nervous system. In neurons, the fine-tuned spatial regulation of gene expression is critical for proper synaptic function; accordingly, several studies have demonstrated that circRNAs exhibit highly compartmentalized localization, specifically within dendrites, axons, and synapses. These spatial localization properties imply the presence of active transport mechanisms, which control the intracellular trafficking of circRNAs. This review highlights the current understanding of circRNA transport in neurons, focusing on the molecular machinery driving synaptic enrichment. We explore the potential role of ribonucleoprotein-based transport as a primary mechanism driving circRNA localization and examine how such spatial distribution influences synaptic plasticity and post-transcriptional gene regulation. Finally, we discuss the clinical implications of these processes, exploring the link between dysregulated RNA transport and the development of neuronal abnormalities.
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
Most biological processes are dynamic, yet experimental methods predominantly rely on steady-state measurements to investigate their underlying mechanisms. RNA localization is a fundamental aspect of eukaryotic cell organization and is dynamically regulated by cells. While extensively studied in specialized cell types for a limited number of candidate RNAs, the general principles governing dynamic RNA localization at a transcriptome-wide scale remain largely unexplored. Existing transcriptome-wide studies provide only a static snapshot of RNAs residing in specific cellular locales, in part due to the limited availability of tools for probing cellular spatial organization at biologically relevant scales. Here, we leverage the high spatial (tens of nanometers) and temporal (minute) resolution of APEX-seq to quantitatively measure the dependence of RNA transport on molecular motors at a transcriptome-wide scale in living cells. We conducted these experiments in the context of the localization of mRNAs to the mitochondria, which are essential for cellular function. Our findings indicate that the majority of nuclear-encoded RNAs encoding mitochondrial proteins localize to the outer mitochondrial membrane (OMM) for local translation. We reveal a crucial role of retrograde dynein-based motor transport in RNA localization, demonstrating that its disruption severely impairs RNA targeting to the OMM. Time-resolved profiling of RNAs at the OMM revealed that localization is an active process, and even a brief disruption of transport for a few minutes results in a dramatic loss of localization. Moreover, we demonstrate that the translation efficiency (TE) of localized RNAs is a critical determinant of RNA localization in the context of motor-driven transport, as RNAs that delocalize following motor-transport perturbations exhibit lower TE. Using our temporal perturbation data, we also developed a spatiotemporal model that utilizes translation kinetics to capture key features of RNA localization dynamics at the OMM. Together, experiments and modeling suggest that the process of local translation at the OMM is kinetically controlled by the cell, and reveal an unappreciated mechanism by which active transport of RNAs enables cells to modulate their translation within minutes through RNA localization control. Our study demonstrates how simultaneously capturing the kinetics of hundreds of transcripts with minute resolution can uncover general principles of cellular and organelle organization. Together, these experiments and modeling reveal how active transport and translation jointly maintain the OMM-localized transcriptome. More broadly, they identify RNA localization to cellular membranes as a rapidly tunable mechanism for controlling local translation, even in non-polarized cells.
Surbhi Sharma, Xuemei Wang, Steven Nguyen et al.· bioRxiv· 0 citations
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
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
Cerebral cortex development is a tightly coordinated sequence of interconnected processes: proliferation of neural progenitors, neuronal migration, neurite differentiation, axonal pathfinding, and synaptogenesis. Traditionally, motor proteins–dyneins, kinesins, and myosins–have been viewed as molecules mediating intracellular transport along the cytoskeleton. Nevertheless, data accumulated over the past decade provide compelling evidence for a fundamentally different, non-transport role of these proteins in nervous system development. This review systematizes current understanding of the non-transport functions of motor proteins at key stages of corticogenesis. We review the molecular mechanisms that enable dyneins, kinesins, and myosins to function as regulators of cortical development. We focus specifically on the causal relationship between disruptions to the non-transport functions of motor proteins and cortical developmental disorders, including microcephaly, lissencephaly, and agenesis of the corpus callosum.
Natalia Mitina, Alexandra D Medyanik, Victor S Tarabykin et al.· Frontiers in Cell and Develo...· 0 citations
How LRRK2-dependent trafficking mechanisms regulate key components of synaptic transmission, including glutamatergic and GABAergic receptors, as well as astrocytic transporters are examined, highlighting how disruption of these processes affects neurotransmitter clearance, receptor activation, and ultimately E/I balance.
Angela Di Iacovo, Chiara D’Agostino, Giulia Casoli et al.· Cellular and molecular neuro...· 0 citations