At the onset of neurogenesis, aRGC amplification and the size of VZ are markedly different between species with a large cortex (i.e., human, macaque, and ferret) and a small cortex (i.e., mouse) ( 3, 12). Given that aRGCs are the origin of excitatory cortical cell lineages, the duration of the amplificative period and the rate of aRGC proliferation will determine the pool size of aRGCs, thus the number of ontogenetic cell lineages and, ultimately, cortex size ( 18). At early stages of cortical development, the abundance of aRGCs increases by self-amplifying divisions, but as neurogenesis starts, aRGCs gradually switch to producing the other cell types.
bRGCs contribute critically to increase neurogenesis and to promote cerebral cortex growth and folding in these species ( 17). In species with large brains such as carnivores and primates, the abundance and proliferation of basal progenitor cells increases massively during development, particularly bRGCs, and the SVZ becomes subdivided into inner SVZ (ISVZ) and outer SVZ (OSVZ) ( 3, 12– 16). Basal progenitors coalesce into a secondary germinal layer, the subventricular zone (SVZ), and produce the majority of cortical excitatory neurons ( 11). Following mitotic division, aRGCs produce either more aRGCs or basal progenitors, namely, intermediate progenitor cells (IPCs) and basal RGCs (bRGCs). The ventricular zone (VZ) is the inner (apical) layer of the embryonic cortex and is essentially composed of apical radial glia cells (aRGCs), the primary type of cortical progenitor cell. Neural stem and progenitor cells in the developing mammalian cerebral cortex are organized in germinal zones. Unfortunately, our understanding of the mechanisms that regulate gene expression and signaling pathway activity across mammalian phylogeny, particularly related to brain evolution, remains limited ( 10). This may have resulted, in part, from the secondary loss of developmental features key for brain size and folding, stemming from gene expression regulation ( 2, 4). In some clades such as New World monkeys and, particularly, rodents, the general trend in evolution toward brain expansion and folding was reversed at some point: Brains evolved, becoming smaller and smoother than those of their ancestors ( 9). More generally, this was achieved by regulating the levels or patterns of expression of highly conserved genes and signaling pathways ( 6, 8). At the molecular level, multiple genes have been identified that emerged specifically in the recent human lineage and promote neural stem cell proliferation and brain growth ( 5– 7). At the cellular level, this seems to result from the increased pool size of neural stem and progenitor cells and their proliferative capacity ( 3, 4). Understanding the cellular and molecular mechanisms of cerebral cortex expansion in mammalian evolution is a major challenge. The mammalian cerebral cortex went through a remarkable expansion in size and folding during evolution from its stem ancestor ( 1), a process recapitulated during embryonic development ( 2). Our results identify a gene selected for secondary loss during mammalian evolution to limit RGC amplification and, potentially, cortex size in rodents. Accordingly, loss of endogenous miR-3607 in ferret reduced RGC proliferation, while overexpression in human cerebral organoids promoted VZ expansion. Experimental expression of miR-3607 in embryonic mouse cortex led to increased Wnt/β-catenin signaling, amplification of radial glia cells (RGCs), and expansion of the ventricular zone (VZ), via blocking the β-catenin inhibitor APC (adenomatous polyposis coli). We show that microRNA miR-3607 is expressed embryonically in the large cortex of primates and ferret, distant from the primate-rodent lineage, but not in mouse. Genetic mechanisms underlying this secondary loss in rodent evolution remain unknown. This process was reversed in the rodent lineage after splitting from primates, leading to smaller and smooth brains. The evolutionary expansion and folding of the mammalian cerebral cortex resulted from amplification of progenitor cells during embryonic development.
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