Come as You R(NA): Post-transcriptional Regulation Will Do the Rest

Recent studies have highlighted the discrepancy between transcriptional regulation and protein levels in the brain, thus placing post-transcriptional mechanisms at the center of neuronal function. RNA molecules are highly versatile and regulated at multiple stages of their lifecycle. This significantly affects both coding and non-coding transcript sequences, asymmetric RNA localization in specific compartments, RNA stability, and resulting protein production. We are beginning to understand the many RNA regulatory pathways in progenitors, developing and mature neurons, and their links with neurological disorders. It all starts in the nucleus with RNA processing regulation – intimately coupled with transcription. For instance, alternative processing such as microexon inclusion, cryptic exons, intron retention or back-splicing reactions and resulting circular RNAs, impacts the spatio-temporal dynamics of transcripts and amplifies the proteome. In the cytoplasm, an increasing number of pathways are now identified to control translation, such as the phase transition of ribonucleoprotein condensates, to fine-tune protein production, in particular at specific synapses.

Advances in -omics technologies have massively accelerated our strive to understand the many contributions of post-transcriptional mechanisms in the central nervous system. This has highlighted the specificity of these processes at different developmental stages, in different cell and synapse types, in response to different stimuli, and their substantial alterations in neurodevelopmental and neurodegenerative disorders. Many of these post-transcriptional regulatory steps are well conserved throughout evolution. Others have emerged exclusively in primates, supporting the compelling hypothesis that post-transcriptional mechanisms could play a pivotal role in species evolution.

This now paves the way to investigate their functional relevance for neuronal circuits and higher cognitive functions. The revolution of CRISPR and the thorough manipulation of gene sub-sequences without interfering with global gene expression provides a means to directly address the role of post-transcriptional events on neuron development and plasticity. We anticipate that a better understanding of the underlying principles of these mechanisms will provide unprecedented insight into various brain functions.

This Research Topic aims to highlight the recent progress on post-transcriptional processes involved in the development, function, and plasticity of brain cells. We welcome Perspective and Review Articles. Themes to be addressed in this Topic include but are not limited to:

- diverse forms of RNA processing (e.g. alternative splicing, RNA editing, chemical modifications) and their functional relevance

- roles of non-coding RNAs (e.g. microRNAs, long non-coding RNAs, circular RNAs)

- mechanisms of RNA export, transport and localization

- mRNA translational control and its local regulation in specific subcellular compartments

- ribonucleoprotein condensates for translational control

- technical challenges for single-cell and single-synapse characterization of post-transcriptional programs

- post-transcriptional regulation across species

Keywords: RNA processing, microexon, non-coding RNA, ribonucleoprotein condensates, local and non-canonical translation regulation, neuron development and plasticity

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