Making sense of mRNA landscapes: Translation control in neurodevelopment

Abstract

Like all other parts of the central nervous system, the mammalian neocortex undergoes temporally ordered set of developmental events, including proliferation, differentiation, migration, cellular identity, synaptogenesis, connectivity formation, and plasticity changes. These neurodevelopmental mechanisms have been characterized by studies focused on transcriptional control. Recent findings, however, have shown that the spatiotemporal regulation of posttranscriptional steps like alternative splicing, mRNA traffic/localization, mRNA stability/decay, and finally repression/derepression of protein synthesis (mRNA translation) have become just as central to the neurodevelopment as transcriptional control. A number of dynamic players act post-transcriptionally in the neocortex to regulate these steps, as RNA binding proteins (RBPs), ribosomal proteins (RPs), long non-coding RNAs, and/or microRNA. Remarkably, mutations in these post-transcriptional regulators have been associated with neurodevelopmental, neurodegenerative, inherited, or often co-morbid disorders, such as microcephaly, autism, epilepsy, intellectual disability, white matter diseases, Rett-syndrome like phenotype, spinocerebellar ataxia, and amyotrophic lateral sclerosis. Here, we focus on the current state, advanced methodologies and pitfalls of this exciting and upcoming field of RNA metabolism with vast potential in understanding fundamental neurodevelopmental processes and pathologies.

Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation

“…These mRNA processing events, commonly known as the ribonome ( Mansfield and Keene, 2009 ), include splicing, alternative polyadenylation, editing, stabilization, temporal silencing, targeted localization, and translation. RBPs, together with ribosomal proteins and non-coding RNAs [e.g., microRNA and long non-coding RNA (lncRNA)], are thought to be the key components of the post-transcriptional machinery since they shape the final output of the ribonome ( Kwan et al, 2012 ; DeBoer et al, 2013 ; Doxakis, 2014 ; Mao et al, 2015 ; Pilaz and Silver, 2015 ; Kraushar et al, 2016 , 2021 ; Ceci et al, 2021 ; Park et al, 2021b ). The array of post-transcriptional network activities indicate that dynamic control of the transcriptome is a multifaceted series of events, necessary for the careful orchestration of the cellular behavior during neocortical development ( Figure 3 ).…”

“…Various RBPs are already recognized as highly important for the protection of progenitors’ neurogenic potentials ( Box 2 ), such as FMRP, Smaug2, Nanos1, Rbfox, and polypyrimidine tract-binding protein 1 (Ptbp1). Since their function during neurogenesis has been previously reviewed in detail ( Pilaz and Silver, 2015 ; Popovitchenko and Rasin, 2017 ; Zahr et al, 2018 , 2019 ; Park et al, 2021b ), we will focus on deciphering the function of RBPs whose fascinating regulatory roles during early neurogenesis have recently become elucidated ( Figure 4 ).…”

“…These cell-intrinsic players, together with extrinsic factors, play an essential role in modulating the information flow from genes to proteins, thereby participating in the diversification of cell function from a fixed numbers of genes ( Halbeisen et al, 2008 ; Ascenzi and Bony, 2017 ). Such coordinated regulatory activity of intrinsic and extrinsic patterns is particularly relevant to instruct the sequential flow of neocortical development ( Kraushar et al, 2015 ; Yuzwa and Miller, 2017 ; Park et al, 2021a , b ).…”

RNA-Binding Proteins and Alternative Splicing Genes Are Coregulated in Human Retinal Endothelial Cells Treated with High Glucose

“…RNA-binding proteins (RBPs) are vital regulators of an mRNA life cycle, including their transcription, splicing export, and transport to degradation, deadenylation, storage, silencing, and mRNA translation (protein synthesis) [ 17 , 18 ]. Along with the spliceosome complex, RBPs have a major role in creating cell-type-specific regulation of alternative splicing [ 10 , 19 , 20 ].…”

Gemin5-dependent RNA association with polysomes enables selective translation of ribosomal and histone mRNAs

“…The dynamic interplay between RBPs and mRNA cis-acting elements regulates translation using distinct mechanisms of action [ 26 – 28 ]. The still underestimated functions of cis-acting regulatory elements, in many cases combining sequence and RNA structure, is exemplified by IRES elements, AU-rich elements (AREs), 5’terminal oligopyrimidine tracts (5’TOP), or the metazoan histone stem-loop (hSL) structures, among others.…”