Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex.

Changes in transcriptional regulation through cis-regulatory elements are thought to drive brain evolution. However, how this impacts the identity of primate cortical neurons is still unresolved. Here, we show that primate-specific cis-regulatory sequences upstream of the Dbx1 gene promote human-like expression in the mouse embryonic cerebral cortex, and this imparts cell identity. Indeed, while Dbx1 is expressed in highly restricted cortical progenitors in the mouse ventral pallium, it is maintained in neurons in primates. Phenocopy of the primate-like Dbx1 expression in mouse cortical progenitors induces ectopic Cajal-Retzius and subplate (SP) neurons, which are transient populations playing crucial roles in cortical development. A conditional expression solely in neurons uncouples mitotic and postmitotic activities of Dbx1 and exclusively promotes a SP-like fate. Our results highlight how transcriptional changes of a single fate determinant in postmitotic cells may contribute to the expansion of neuronal diversity during cortical evolution.

Enhanced Abventricular Proliferation Compensates Cell Death in the Embryonic Cerebral Cortex.

Loss of neurons in the neocortex is generally thought to result in a final reduction of cerebral volume. Yet, little is known on how the developing cerebral cortex copes with death of early-born neurons. Here, we tackled this issue by taking advantage of a transgenic mouse model in which, from early embryonic stages to mid-corticogenesis, abundant apoptosis is induced in the postmitotic compartment. Unexpectedly, the thickness of the mutant cortical plate at E18.5 was normal, due to an overproduction of upper layer neurons at E14.5. We developed and simulated a mathematical model to investigate theoretically the recovering capacity of the system and found that a minor increase in the probability of proliferative divisions of intermediate progenitors (IPs) is a powerful compensation lever. We confirmed experimentally that mutant mice showed an enhanced number of abventricular progenitors including basal radial glia-like cells and IPs. The latter displayed increased proliferation rate, sustained Pax6 expression and shorter cell cycle duration. Altogether, these results demonstrate the remarkable plasticity of neocortical progenitors to adapt to major embryonic insults via the modulation of abventricular divisions thereby ensuring the production of an appropriate number of neurons.