Abstract
SummaryCerebral cortical development is controlled by key transcription factors that specify the neuronal identities in the different layers. The mechanisms controlling their expression in distinct cells are only partially known. We investigated the expression and stability of Tbr1, Bcl11b, Fezf2, Satb2, and Cux1 mRNAs in single developing mouse cortical cells. We observe that Satb2 mRNA appears much earlier than its protein and in a set of cells broader than expected, suggesting an initial inhibition of its translation, subsequently released during development. Mechanistically, Satb2 3′UTR modulates protein translation of GFP reporters during mouse corticogenesis. We select miR-541, a eutherian-specific miRNA, and miR-92a/b as the best candidates responsible for SATB2 inhibition, being strongly expressed in early and reduced in late progenitor cells. Their inactivation triggers robust and premature SATB2 translation in both mouse and human cortical cells. Our findings indicate RNA interference as a major mechanism in timing cortical cell identities.
Highlights
The mammalian neocortex consists of six cell layers (I–VI) generated by radial migration of neuroblasts following an inside-out mechanism (Greig et al, 2013)
Glutamatergic projection neurons are formed after the generation of layer I neurons in two main neurogenetic waves: deep projection neurons (DPNs) of layers V–VI are generated first, followed by superficial projection neurons (SPNs) of the supra-granular layers II–III (Figure 1A)
Satb2 is co-transcribed with other cell identity transcription factors (CITFs) in early cortical cells before its translation Since DPNs and SPNs are sequentially generated in an inside-out fashion from embryonic day 11.5 (E11.5) to E17.5 in mouse (Figure 1A), we expect that the mRNA of CITFs is regulated in selected progenitor cell (PC) in this time window
Summary
The mammalian neocortex consists of six cell layers (I–VI) generated by radial migration of neuroblasts following an inside-out mechanism (Greig et al, 2013). The expression of a few cell identity transcription factors (CITFs) is necessary to impart distinct cell fates, with TBR1, BCL11B, FEZF2, SATB2, and CUX1 playing an important role among them (Alcamo et al, 2008; Cubelos et al., 2010; Hevner et al, 2001, 2003; Leone et al, 2015; Srinivasan et al, 2012) These factors may initially establish early mutual activating or repressive interactions; beyond this early phase, depending on the cell context and the timing of corticogenesis, some of these interactions may change and combinatorial action may ensue to refine terminal cell phenotype (Alcamo et al, 2008; Britanova et al, 2008; Chen et al, 2008; Harb et al, 2016; Jaitner et al, 2016; McKenna et al, 2015). The exact mechanisms dictating the timely expression of CITFs in one given PC and its progeny is still under scrutiny
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