Abstract
Neuronal morphogenesis, integration into circuits, and remodeling of synaptic connections occur in temporally and spatially defined steps. Accordingly, the expression of proteins and specific protein isoforms that contribute to these processes must be controlled quantitatively in time and space. A wide variety of post-transcriptional regulatory mechanisms, which act on pre-mRNA and mRNA molecules contribute to this control. They are thereby critically involved in physiological and pathophysiological nervous system development, function, and maintenance. Here, we review recent findings on how mRNA metabolism contributes to neuronal development, from neural stem cell maintenance to synapse specification, with a particular focus on axon growth, guidance, branching, and synapse formation. We emphasize the role of RNA-binding proteins, and highlight their emerging roles in the poorly understood molecular processes of RNA editing, alternative polyadenylation, and temporal control of splicing, while also discussing alternative splicing, RNA localization, and local translation. We illustrate with the example of the evolutionary conserved Musashi protein family how individual RNA-binding proteins are, on the one hand, acting in different processes of RNA metabolism, and, on the other hand, impacting multiple steps in neuronal development and circuit formation. Finally, we provide links to diseases that have been associated with the malfunction of RNA-binding proteins and disrupted post-transcriptional regulation.
Highlights
Developmental assembly of neural circuits occurs through precisely orchestrated cellular events for the specification, differentiation, and morphogenesis of neurons
The messenger RNAs (mRNAs) isoforms with a specific localization usually have a longer 3′untranslated regions (UTRs), indicating that 3′UTR lengthening confers an enhanced potential for spatial regulation (Tushev et al, 2018). mRNA stabilization and localization are controlled by different RNA-binding proteins (RBPs) that bind to the 3′UTR, together forming macromolecular complexes called RNA granules. mRNA granules contain several RBPs, such as zip-code binding protein 1 (ZBP1), FMRP, or Staufen2, which are responsible for localization, stabilization, and regulation of translation (Kiebler and Bassell, 2006). mRNA localization and local translation are essential for neuronal development and plasticity (Lin and Holt, 2008; Holt and Schuman, 2013; Shigeoka et al, 2013; Jung et al, 2014; Glock et al, 2017; Cioni et al, 2018a; Biever et al, 2019; Holt et al, 2019), and will be discussed in more detail below
It will be exciting to determine in the future whether coupling of APA and alternative splicing (AS) is a widespread feature during mRNA biogenesis in the developing nervous system
Summary
Developmental assembly of neural circuits occurs through precisely orchestrated cellular events for the specification, differentiation, and morphogenesis of neurons. Beyond transcriptional control of gene expression, post-transcriptional mechanisms confer multiple additional layers and means of regulation for achieving protein synthesis at the right time and place in developing neurons We refer to these mechanisms, which are introduced below, as “RNA metabolism.”. RBPs are, critically involved in the expansion of proteome diversity and of proteome function in neurons, and in the rapid and localized control of neuronal gene expression These processes are essential for coordinating axon and dendrite growth, guidance, targeting, and synapse formation. We will discuss how RNA metabolism and its control by RBPs guide key steps of neuronal wiring, with a special focus on axon and synapse development Given their essential functions in neural circuit assembly, it is not surprising that mutations in RBPs have been associated with neurodevelopmental disorders in humans. Given the breadth of identified mechanisms and molecules, we are thereby focusing on chosen examples rather than aiming at providing a comprehensive review of the field
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