Non-linear heterochronic scaling of neurogenesis for species-specific dosing of cortical excitatory subtypes
All animals have specialized brain structures with a neuronal composition optimized for their survival and adaptation. The mammals share the laminar structure of the cerebral cortex, where a certain repertoire of excitatory neuron subtypes is arranged in specific tangential layers. However, the quantitative balance of subtypes is highly specialized in each species due to unknown developmental mechanisms. It is of particular interest to understand how the relatively conserved process of mammalian corticogenesis is modified in each species to achieve an optimized neuronal composition. Here, we show that fine-tuning the temporal progression of neurogenesis is the critical mechanism of the species-specific neuronal repertoire through our comparative study of mouse and rat cortical excitatory neurogenesis. Clonal tracing of individual progenitors revealed that rats produce more deep layer (DL) subtypes than mice, but both species produce essentially the same number of upper layer (UL) neurons. Such subtype-specific dosage optimization is mediated by the selective expansion of the early neurogenetic window for DL production in rats, as revealed by our neuronal birthdating and single cell transcriptomics. We found that the temporal neurogenetic status of the progenitors is encoded, at least in part, by Ccnd1 expression, as evidenced by the precocious UL production upon Ccnd1 knockdown in the rat mid-neurogenetic phase, when significant expression is maintained at levels comparable to the earlier phase in mice. Collectively, these results suggest that the closely related rodents, mouse and rat, construct their cortical structure with specific neuronal composition through the pinpointed specialization in developmental progression while maintaining the basic framework of the inside-out sequence of cortical excitatory neurogenesis. This study used mice and rats, the most common laboratory mammals with a close evolutionary relationship, to reveal the detailed molecular and cellular mechanisms behind the fine-tuning of cell composition in the cerebral cortex. Such a detailed comparison dissected the specialized and unchanged processes of corticogenesis during the evolutionary divergence of the two species. This further provides insights into the evolvability and developmental constraints of mammalian corticogenesis. Overall design: Primary cells derived from rat embryonic cerebral cortex