Size and folding of the cerebral cortex increased massively during mammalian evolution leading to the current diversity of brain morphologies. Various subtypes of neural stem and progenitor cells have been proposed to contribute differently in regulating thickness or folding of the cerebral cortex during development, but their specific roles have not been demonstrated. We report that the controlled expansion of unipotent basal progenitors in mouse embryos led to megalencephaly, with increased surface area of the cerebral cortex, but not to cortical folding. In contrast, expansion of multipotent basal progenitors in the naturally gyrencephalic ferret was sufficient to drive the formation of additional folds and fissures. In both models, changes occurred while preserving a structurally normal, six-layered cortex. Our results are the first experimental demonstration of specific and distinct roles for basal progenitor subtypes in regulating cerebral cortex size and folding during development underlying the superior intellectual capability acquired by higher mammals during evolution.

Neurod1 is a transcription factor involved in several developmental programs of the gastrointestinal tract, pancreas, neurosensory, and central nervous system. In the brain, Neurod1 has been shown to be essential for neurogenesis as well as migration, maturation, and survival of newborn neurons during development and adulthood. Interestingly, Neurod1 expression is maintained in a subset of fully mature neurons where its function remains unclear. To study the role of Neurod1, systems are required that allow the temporal and spatial genetic manipulation of Neurod1-expressing cells. To this aim, we have generated four Neurod1-CreER(T2) mouse lines in which CreER(T2) expression, although at different levels, is restricted within areas of physiological Neurod1 expression and Neurod1 positive cells. In particular, the different levels of CreER(T2) expression in different mouse lines offers the opportunity to select the one that is more suited for a given experimental approach. Hence, our Neurod1-CreER(T2) lines provide valuable new tools for the manipulation of newborn neurons during development and adulthood as well as for studying the subpopulation of mature neurons that retain Neurod1 expression throughout life. In this context, we here report that Neurod1 is not only expressed in immature newborn neurons of the adult hippocampus, as already described, but also in fully mature granule cells of the dentate gyrus.