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Cortical neurogenesis follows a simple lineage: apical radial glia cells (RGCs) generate basal progenitors, and these produce neurons. How this occurs in species with expanded germinal zones and a folded cortex, such as human, remains unclear. We used single-cell RNA sequencing from individual cortical germinal zones in ferret and barcoded lineage tracking to determine the molecular diversity of progenitor cells and their lineages. We identified multiple RGC classes that initiate parallel lineages, converging onto a common class of newborn neuron. Parallel RGC classes and transcriptomic trajectories were repeated across germinal zones and conserved in ferret and human, but not in mouse. Neurons followed parallel differentiation trajectories in the gyrus and sulcus, with different expressions of human cortical malformation genes. Progenitor cell lineage multiplicity is conserved in the folded mammalian cerebral cortex.

The human brain is characterized by the large size and intricate folding of its cerebral cortex, which are fundamental for our higher cognitive function and frequently altered in pathological dysfunction. Cortex folding is not unique to humans, nor even to primates, but is common across mammals. Cortical growth and folding are the result of complex developmental processes that involve neural stem and progenitor cells and their cellular lineages, the migration and differentiation of neurons, and the genetic programs that regulate and fine-tune these processes. All these factors combined generate mechanical stress and strain on the developing neural tissue, which ultimately drives orderly cortical deformation and folding. In this review we examine and summarize the current knowledge on the molecular, cellular, histogenic, and mechanical mechanisms that are involved in and influence folding of the cerebral cortex, and how they emerged and changed during mammalian evolution. We discuss the main types of pathological malformations of human cortex folding, their specific developmental origin, and how investigating their genetic causes has illuminated our understanding of key events involved. We close our review by presenting the animal and in vitro models of cortex folding that are currently used to study these devastating developmental brain disorders in children, and what are the main challenges that remain ahead of us to fully understand brain folding.