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Intact DNA strands can be found in fossils, while scientists sometimes struggle to keep RNA intact under laboratory conditions. The structural variations between RNA and DNA underlie the differences in their stability and longevity. Because DNA is double-stranded, it is inherently more stable. The single-stranded structure of RNA is less stable but also more flexible and can form weak internal bonds. Additionally, most RNAs in the cell are relatively short, while DNA can be up to 250 million...
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Neuronal activity triggers widespread changes in RNA stability.

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    Neuronal activity regulates gene expression by controlling RNA stability, not just transcription. This process, mediated by HuD protein, is crucial for brain development and implicated in neurodevelopmental disorders like autism spectrum disorder (ASD).

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    Area of Science:

    • Neuroscience
    • Molecular Biology
    • Genetics

    Background:

    • Neuronal activity is known to influence gene expression for brain development and synaptic plasticity.
    • While transcriptional regulation is well-studied, the impact of neuronal activity on the entire RNA life cycle is less understood.

    Purpose of the Study:

    • To investigate the holistic effects of neuronal activity on RNA metabolism in neurons.
    • To identify key mechanisms and regulators of activity-dependent RNA regulation.
    • To explore the role of these mechanisms in neurodevelopmental disorders.

    Main Methods:

    • In vitro and in vivo experiments to study RNA metabolism.
    • Analysis of 3'UTR mRNA motifs and machine learning to identify RNA-binding proteins.
    • Investigation of HuD protein's role in activity-dependent mRNA stabilization.
    • Study of variants associated with autism spectrum disorder (ASD).

    Main Results:

    • Neuronal activity impacts multiple stages of RNA metabolism, with RNA stability being a significant regulator for ~15% of activity-dependent genes.
    • Specific 3'UTR mRNA motifs were identified that modulate activity-dependent mRNA stability.
    • The RNA-binding protein HuD was identified as a key regulator, stabilizing hundreds of transcripts in response to neuronal activity.
    • Neuronal activity reorganizes HuD-interacting proteins, influencing mRNA stability and translation.
    • Disruptions in activity-dependent mRNA stability are linked to variants associated with ASD and other neurodevelopmental disorders.

    Conclusions:

    • RNA stability is a critical, underappreciated mechanism for stimulus-responsive gene regulation in neurons.
    • HuD plays a central role in mediating activity-dependent mRNA stability.
    • Aberrant mRNA stability mechanisms may contribute to the pathophysiology of neurodevelopmental disorders.