Transcriptional Control of Neocortical Size and Microcephaly.

The mammalian neocortex differs vastly in size and complexity between mammalian species, yet the mechanisms that lead to an increase in brain size during evolution are not known. We show here that two transcription factors coordinate gene expression programs in progenitor cells of the neocortex to regulate their proliferative capacity and neuronal output in order to determine brain size. Comparative studies in mice, ferrets and macaques demonstrate an evolutionary conserved function for these transcription factors to regulate progenitor behaviors across the mammalian clade. Strikingly, the two transcriptional regulators control the expression of large numbers of genes linked to microcephaly suggesting that transcriptional deregulation as an important determinant of the molecular pathogenesis of microcephaly, which is consistent with the finding that genetic manipulation of the two transcription factors leads to severe microcephaly. Summary:The neocortex varies in size and complexity among mammals due to the tremendous variability in the number and diversity of neuronal subtypes across species 1,2 . The increased cellular diversity is paralleled by the expansion of the pool of neocortical progenitors 2-5 and the emergence of indirect neurogenesis 6 during brain evolution. The molecular pathways that control these biological processes and are disrupted in neurological and psychiatric disorders remain largely unknown. Here we show that the transcription factors BRN1 (POU3F3) and BRN2 (POU3F2) act as master regulators of the transcriptional programs in progenitors linked to neuronal specification and neocortex expansion. Using genetically modified lissencephalic and gyrencephalic animals, we found that BRN1/2 establish transcriptional programs in neocortical progenitors that control their proliferative capacity and the switch from direct to indirect neurogenesis. Functional studies in genetically modified mice and ferrets show that BRN1/2 act in concert with NOTCH and primary microcephaly genes to regulate progenitor behavior. Analysis of transcriptomics data from genetically modified macaques provides evidence that these molecular pathways are conserved in non-human primates. Our findings thus establish a mechanistic link between BRN1/2 and genes linked to microcephaly and demonstrate that BRN1/2 are central regulators of gene expression programs in neocortical progenitors critical to determine brain size during evolution.