MicroRNA profiling of mouse cortical progenitors and neurons reveals miR-486-5p as a regulator of neurogenesis

Abstract

MicroRNAs (miRNAs) are short (∼22 nt) single-stranded non-coding RNAs that regulate gene expression at the post-transcriptional level. Over recent years, many studies have extensively characterized the involvement of miRNA-mediated regulation in neurogenesis and brain development. However, a comprehensive catalog of cortical miRNAs expressed in a cell-specific manner in progenitor types of the developing mammalian cortex is still missing. Overcoming this limitation, here we exploited a double reporter mouse line previously validated by our group to allow the identification of the transcriptional signature of neurogenic commitment and provide the field with the complete atlas of miRNA expression in proliferating neural stem cells, neurogenic progenitors and newborn neurons during corticogenesis. By extending the currently known list of miRNAs expressed in the mouse brain by over twofold, our study highlights the power of cell type-specific analyses for the detection of transcripts that would otherwise be diluted out when studying bulk tissues. We further exploited our data by predicting putative miRNAs and validated the power of our approach by providing evidence for the involvement of miR-486 in brain development.

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

“…Other miRNAs are necessary for progenitor proliferation. miR-486a/b-5p is downregulated as progenitors transition from self-replenishing proliferation to neurogenesis; ectopic expression in radial glia prolongs the proliferative stage, leading to over-expansion of the progenitor pool at the expense of neuron number ( Dori et al, 2020 ). Experiments in human induced pluripotent stem cells (iPSCs) have identified the primate-specific miR-934 as another potential regulator of this transition, with miR-934 activity during neural induction of stem cells correlating to neurogenesis and decreased numbers of proliferative progenitors ( Prodromidou et al, 2020 ).…”

miRNA-486-5p: signaling targets and role in non-malignant disease

“…miR-486-5p is also implicated in neurogenesis. Dori et al isolated discrete populations of neural progenitor cells (proliferative progenitors that expand the stem cell pool and differentiative progenitors that generate neurons) and profiled global miRNA expression during cortical development [ 131 ]. miR-486-5p expression is transiently downregulated in differentiative progenitors compared with proliferative progenitors and neurons, termed an ‘off-switch’ transcript.…”

“…miR-486-5p expression is transiently downregulated in differentiative progenitors compared with proliferative progenitors and neurons, termed an ‘off-switch’ transcript. In utero delivery of a locked nucleic acid miR-486-5p inhibitor to mice at embryonic day 13.5 (the developmental stage, where cortical progenitor cells are mostly proliferative progenitors) increases the proportion of cortical progenitor cells at the expense of neurons without affecting neuron migration or survival [ 131 ]. These findings suggest that miR-486-5p regulates cell fate in neurogenesis, but the precise targets of miR-486-5p in cortical development remain unknown.…”

Epigenetic Regulation of Neural Stem Cells: The Emerging Role of Nucleoporins

“…94 An additional layer of gene expression control, provided by NPC and Nups, occurs through the regulation of miRNAs, which play key roles in modulation of both embryonic and adult neurogenesis. 38,39 In this context, Nups provide a platform control for miRNA precursor biogenesis and export through the NPC. 95 Other Nups do not control miRNA biogenesis but participate directly in miRNA-mediated silencing.…”

“… 38 A specific miRNA signature associated with neurogenic commitment of progenitors during embryonal cortical development was also recently described. 39 MiR‐146a was found to be critical for both proper differentiation of NSCs during brain development and for the regulation of postnatal hippocampal‐dependent memory. 40 Other miRNAs were identified as regulators to switch between NSC proliferation and differentiation.…”