Neocortical Expansion Due to Increased Proliferation of Basal Progenitors Is Linked to Changes in Their Morphology

The evolutionary expansion of the mammalian neocortex (Ncx) is thought to be linked to increased proliferative capacity of basal progenitors (BPs) and their neurogenic capacity. Here, by quantifying BP morphology in the developing Ncx of mouse, ferret, and human, we show that increased BP proliferative capacity is linked to an increase in BP process number. We identify human membrane-bound PALMDELPHIN (PALMD-Caax) as an underlying factor, and we show that it drives BP process growth and proliferation when expressed in developing mouse and ferret Ncx. Conversely, CRISPR/Cas9-mediated disruption of PALMD or its binding partner ADDUCIN-γ in fetal human Ncx reduces BP process numbers and proliferation. We further show that PALMD-induced processes enable BPs to receive pro-proliferative integrin-dependent signals. These findings provide a link between BP morphology and proliferation, suggesting that changes in BP morphology may have contributed to the evolutionary expansion of the Ncx. [Display omitted] •Basal progenitors (BPs) in the human neocortex have six distinct morphotypes•Increasing BP proliferative capacity is correlated with increasing BP process numbers•Membrane-bound PALMD is required for and sufficient to increase BP processes•Induction of BP processes by PALMD promotes BP proliferation via integrin signaling Huttner and colleagues show that an increase in the number of neural progenitor cell processes underlies the proliferative capacity of this population. Expression of human membrane-bound PALMDELPHIN increases the number of progenitor processes and activates integrin signaling, leading to enhanced progenitor proliferation and an increase in upper-layer neurons.