MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

Abstract

Characterizing the diverse cell types that make up the nervous system is essential for understanding how the nervous system is structured and ultimately how it functions. The astonishing range of cellular diversity found in the nervous system emerges from a small pool of neural progenitor cells. These progenitors and their neuronal progeny proceed through sequential gene expression programs to produce different cell lineages and acquire distinct cell fates. These gene expression programs must be tightly regulated in order for the cells to achieve and maintain the proper differentiated state, remain functional throughout life, and avoid cell death. Disruption of developmental programs is associated with a wide range of abnormalities in brain structure and function, further indicating that elucidating their contribution to cellular diversity will be key to understanding brain health. A growing body of evidence suggests that tight regulation of developmental genes requires post-transcriptional regulation of the transcriptome by microRNAs (miRNAs). miRNAs are small non-coding RNAs that function by binding to mRNA targets containing complementary sequences and repressing their translation into protein, thereby providing a layer of precise spatial and temporal control over gene expression. Moreover, the expression profiles and targets of miRNAs show great specificity for distinct cell types, brain regions and developmental stages, suggesting that they are an important parameter of cell type identity. Here, we provide an overview of miRNAs that are critically involved in establishing neural cell identities, focusing on how miRNA-mediated regulation of gene expression modulates neural progenitor expansion, cell fate determination, cell migration, neuronal and glial subtype specification, and finally cell maintenance and survival.

microRNA Heterogeneity, Innate-Immune Defense and the Efficacy of SARS-CoV-2 Infection—A Commentary

“…This individual diversity in genomic expression is reflected in part by the substantial heterogeneity of miRNA species abundance, sequence variety, and complexity in human cells, tissues, and physiological systems [ 11 , 12 , 13 , 14 , 35 , 36 , 39 ]. These single-stranded RNAs (ssRNAs) represent a ubiquitous form of sncRNAs found in all eukaryotic cells and tissues; their major function is to bind with single-stranded messenger RNA (mRNA) targets to form a transient miRNA-mRNA duplex which is rapidly degraded by ribonucleoproteins and nucleases within the cell, thus preventing productive translation at the eukaryotic 80S ribosome [ 1 , 2 , 3 , 4 , 5 , 7 ]. Therefore, mammalian miRNAs predominantly function to decrease target mRNA (ssRNA) levels, although several other miRNA- and Argonaute-2 (AGO2)-mediated gene regulatory mechanisms have been described [ 22 , 23 , 45 ].…”

“…miRNAs (microRNAs) are a family of short non-coding RNA (sncRNA) 18–23 nucleotides (nt) in length that regulate gene expression in human cells using a post-transcriptional regulatory mechanism [ 1 ]. Typically generated by RNA polymerase II (RNAPII)-based transcription from genomic DNA and pre-miRNA processing mechanisms, human cells typically contain about ~2650 different miRNA species, although miRNA populations vary widely amongst different cell types and amongst individuals of the same species (miRBase v.22; GENCODE data v.29) [ 2 , 3 , 4 , 5 ]. Different cell types contain a different complement of miRNAs that vary in abundance, speciation, and complexity during development, homeostatic day-to-day function, aging, and disease [ 4 , 5 , 6 ].…”

“…Typically generated by RNA polymerase II (RNAPII)-based transcription from genomic DNA and pre-miRNA processing mechanisms, human cells typically contain about ~2650 different miRNA species, although miRNA populations vary widely amongst different cell types and amongst individuals of the same species (miRBase v.22; GENCODE data v.29) [ 2 , 3 , 4 , 5 ]. Different cell types contain a different complement of miRNAs that vary in abundance, speciation, and complexity during development, homeostatic day-to-day function, aging, and disease [ 4 , 5 , 6 ]. Although multiple mechanisms exist, the general mode of miRNA action is to bind to the 3′-untranslated region (3’-UTR) of their target messenger RNA (mRNA) via complementary base-pair interactions; in doing so, this miRNA-mRNA hybrid: (i) Can impair or block normal mRNA transit through the cleft of the eukaryotic 80S ribosome [ 4 , 5 , 7 ]; (ii) represses gene expression post-transcriptionally by destabilizing and down-regulating their target mRNA(s) [ 1 , 3 , 4 ]; and (iii) reduce protein production and repress genetic information encoded in that target mRNA [ 1 , 2 , 3 , 4 , 5 ].…”

“…Different cell types contain a different complement of miRNAs that vary in abundance, speciation, and complexity during development, homeostatic day-to-day function, aging, and disease [ 4 , 5 , 6 ]. Although multiple mechanisms exist, the general mode of miRNA action is to bind to the 3′-untranslated region (3’-UTR) of their target messenger RNA (mRNA) via complementary base-pair interactions; in doing so, this miRNA-mRNA hybrid: (i) Can impair or block normal mRNA transit through the cleft of the eukaryotic 80S ribosome [ 4 , 5 , 7 ]; (ii) represses gene expression post-transcriptionally by destabilizing and down-regulating their target mRNA(s) [ 1 , 3 , 4 ]; and (iii) reduce protein production and repress genetic information encoded in that target mRNA [ 1 , 2 , 3 , 4 , 5 ]. The majority of miRNA–mRNA interactions, biogenesis, and function in any human cell remain largely unidentified, poorly characterized, and incompletely understood, although rapid research progress is being made.…”

“…Multiple miRNA-mRNA interactions are known to be especially important in human neurological health and disease [ 2 , 5 , 6 ]. Interestingly, as single-stranded RNAs, messenger RNA (mRNA) and single-stranded viral RNA (ssvRNA) appear to be interchangeable targets for miRNA and/or sncRNA action [ 3 , 4 , 5 , 6 , 7 , 8 ]. That is, any single-stranded RNA or ssvRNA encountered by a host miRNA that is sufficiently complementary will be down-regulated, and its potential biological activity will be accordingly diminished.…”