The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

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.

RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration

“…Once transcribed, indeed, messengers are subjected to splicing and polyadenylation, and are eventually moved to the cytoplasm as components of ribonucleoprotein complexes (RNPs), often referred to as granules, many kinds of which have been described [ 75 ]. Actually, in the cells, messengers probably exist exclusively inside these specialized complexes, wherein some proteins directly bind RNAs ( Figure 1 , proteins indicated as “a” and “b”), while others are part of the RNPs because they interact with each other, forming oligomers ( Figure 1 , proteins indicated as “c”) [ 8 , 76 ].…”

“…Post-transcriptional control actually includes multiple steps of regulation, some of which have been studied in detail (i.e., alternative splicing, RNA localization, and local translation), while others, such as RNA editing and alternative polyadenylation, still remain quite elusive [ 8 ]. In particular, polyadenylation seems to have a double-fold role in the metabolism of mRNA, because the length and composition of the 3′-UTR depend on the site of the poly(A) tail addition, and because mRNA’s half-life and its translatability are influenced by the length of the poly(A) [ 8 , 55 , 57 , 59 , 60 ]. Moreover, during the maturation of the 3′-UTR, a tissue-specific mechanism named alternative cleavage and polyadenylation (APA) may create different versions of the mRNA endowed with specific characteristics of regulation [ 77 ].…”

“…The choice of alternative exons allows the production of different protein isoforms, but also can change the regulatory elements located in the 3′-UTR, thus modifying both the final localization of the messengers and the timing of their translation. For example, BDNF and CaMKIIα mRNA isoforms bearing 3′-UTRs, which are shorter and lack dendritic targeting elements (DTEs), do not reach dendrites [ 8 ]. Interestingly, local splicing has been suggested to occur in dendrites of living neurons, indicating local control of 3′-UTR diversity [ 62 ].…”

“…As long as it concerns Staufen (Stau), transport mediated by this protein is based on microtubule activity, as well as kinesin motors [ 109 ]. In the mammalian brain, Stau-mediated transport, in some cases, is dependent on the presence, in mRNAs, of specific introns retained during splicing; for example, only Calmodulin3 (Calm3) mRNA isoform with a longer 3′-UTR and the CaMKII mRNA isoform, which retains intron 16, can reach dendrites by binding Stau2 [ 8 , 110 ].…”

“…As in the case of the DNA–protein interactions that regulate transcription, RNA destiny strictly depends on nucleic acid–protein complexes, and, in particular, on RNA-binding proteins (RBPs) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. As for many other properties of RNA, we can hypothesize that its ability to interact with proteins that regulate its expression is a present-day remnant of an early-life biochemical “RNA world” in which genetic information was stored in RNA molecules [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”