A eutherian-specific microRNA controls the translation of Satb2 in a model of cortical differentiation

Abstract

Summary Cerebral 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.

Expression of Satb2 in adult brain of key non-mammalian vertebrates: insights from evolution

“…Con rming this, in the mouse the early production of Satb2 protein redirects commissural axons from layers II-III to the anterior commissure, rather than to the corpus callosum (Paolino et al 2020). In eutherian cortical cells, it has been described that Satb2 mRNA appears in more cells and much earlier than its protein, suggesting that at early stages of development its translation can be inhibited (Martins et al 2021). Furthermore, in the early mammalian neocortex, Satb2 binds to the Bcl11b promoter, preventing its expression, and it is LMO4 which removes this inhibition at later stages (Alcamo et al 2008;Britanova et al 2008;Harb et al 2016).…”

“…In the pallium Satb2 has been shown to be expressed with other cell identity transcription factors (CITF genes) in birds, reptiles and mammals (Nomura et al 2018;Tosches et al 2018;Tosches and Laurent 2019). In mammals, Satb2 was abundantly expressed in all six layers of the neocortex (Britanova et al 2005(Britanova et al , 2008Alcamo et al 2008;Nielsen et al 2010;Balamotis et al 2012;Zhang et al 2012;Huang et al 2013;Martins et al 2021), being expressed in the intracortical projection cells through the corpus callosum (Paolino et al 2018), repressing the identity of extracortical projection neurons in these cells. At the same time, Satb2 is also required for the development of these cells, activating Fezf2 and Sox5, both essential for their development.…”

Evolution of genetic mechanisms regulating cortical neurogenesis

“…MiRNAs are important also in brain evolution, via the differential expression of conserved miRNAs or via the emergence of new ones, as is the case of a eutherian‐specific cluster containing miRNAs involved in the acquisition of neuronal identity (Diaz et al., 2020; Martins et al., 2021). The proliferation of NPCs and the emergence of features key in cortical expansion and gyrification, such as the expansion of the OSVZ, are affected by the evolution of posttranscriptional regulation by miRNAs.…”

“…The differential timing in neuronal maturation programs between marsupials and eutherians may account for these differences, as a substantial delay in Satb2 expression in mouse seems to impact the fate of projection neurons (Kozulin et al, 2022;Paolino et al, 2020;Suárez et al, 2018). This may be related to a new regulation by miR-541 (Martins et al, 2021).…”

Expression of Satb2 in adult brain of key non-mammalian vertebrates: insights from evolution

“…Alcamo et al 2008;Nielsen et al 2010;Balamotis et al 2012;Zhang et al 2012;Huang et al 2013;Martins et al 2021). In the mouse, it participates in an antagonistic genetic interaction with the transcription factor Ctip2 to subdivide cortical progenitors into functionally distinct groups(Alcamo et al 2008;Britanova et al 2008), With Satb2 being expressed in the intracortical projection cells through the corpus callosum(Paolino et al 2018).…”