Translational control in cortical development

Abstract

Differentiation of specific neuronal types in the nervous system is worked out through a complex series of gene regulation events. Within the mammalian neocortex, the appropriate expression of key transcription factors allocates neurons to different cortical layers according to an inside-out model and endows them with specific properties. Precise timing is required to ensure the proper sequential appearance of key transcription factors that dictate the identity of neurons within the different cortical layers. Recent evidence suggests that aspects of this time-controlled regulation of gene products rely on post-transcriptional control, and point at micro-RNAs (miRs) and RNA-binding proteins as important players in cortical development. Being able to simultaneously target many different mRNAs, these players may be involved in controlling the global expression of gene products in progenitors and post-mitotic cells, in a gene expression framework where parallel to transcriptional gene regulation, a further level of control is provided to refine and coordinate the appearance of the final protein products. miRs and RNA-binding proteins (RBPs), by delaying protein appearance, may play heterochronic effects that have recently been shown to be relevant for the full differentiation of cortical neurons and for their projection abilities. Such heterochronies may be the base for evolutionary novelties that have enriched the spectrum of cortical cell types within the mammalian clade.

Keywords: RNA binding protein; cortex; development; evolution; microRNA.

Figure 1

miRs, RBP, and RP action in mammalian neocortex. Neocorticogenesis is depicted from NECs to early and late corticogenesis, during the generation of cortical cell layers (L1–L6). The different symbols represent the inhibitory action, exerted by miRs or RBPs, on mRNAs of the indicated genes (or the release of this inhibition), that allow cell state transitions, for some examples detailed in the text. At the bottom, the dynamic ”ribosome signature” is also illustrated, with different colors symbolizing the changing repertoire of RPs and mRNAs recruited on polysomes. SOX2⁺: apical radial glia. TBR2⁺: basal/outer radial glia. CR, Cajal-Retzius cell; GC, granule cell; PN, pyramidal neuron; SP, subplate; SVZ, subventricular zone; VZ, ventricular zone.

Figure 2

miR 397/410 cluster expression in mouse cortical NPCs. (A) Average expression of Mirg miRs in mouse NPCs (calculated from DIV10 to DIV26) as compared to expression in embryonic stem cells (mESCs). In light blue, the Mirg miRs. The two dotted red lines indicate the median expression levels in NPCs and mESCs; Only three out of 47 miRNAs (mmu-miR-544-3p, mmu-miR-496a-5p, and mmu-miR-299b-3p) are expressed at a lower level in both NPCs and mESCs. The dotted blue rectangle indicates the 10 more expressed miRs of Mirg. RPM, reads per million. (B) Heatmap shows the expression of the miRs from the blue dotted rectangle in (A). Day in vitro (DIV) is the time in culture; DIV0 is the onset of the neuralization protocol. DIV10-DIV16 roughly correspond to mouse E10-E16 (Martins et al., 2021). (C–F) KEGG Gene Ontology (GO) enrichment of mRNAs targeted in silico by selected miRs. In silico miR-mRNA interaction was achieved by the TarPmiR tool (Ding et al., 2016) using the miRwalk online resource (http://mirwalk.umm.uni-heidelberg.de). RPM, reads per million. Pop.Hits, number of genes of the GO term. Count, the number of genes enriched in the GO term. FDR, false discovery rate. Data were obtained from Martins et al. (2021).