Epifanova, E. | bioRxiv Science

bioRxiv2026

Evolution Shapes Cortical Interneuron Migration

The cerebral cortex comprises excitatory neurons and inhibitory interneurons originating from distinct forebrain regions. During migration, cortical interneurons (cINs) interact dynamically with neighbouring cells and their microenvironment, contributing to cortical architecture. However, how evolutionary changes in cIN migration shape species-specific cortical development remains unclear. Comparative analyses in mouse, ferret, and human models revealed a conserved migratory sequence but distinct behaviours: human cINs migrate slower, display increased leading-process branching, and exhibit more frequent homotypic repulsive interactions than their mouse and ferret counterparts. These features promote dispersed cortical invasion of cINs in humans and ferrets, contrasting with the stream-like migration observed in mice. Mechanistically, elevated expression of the cytosolic carboxypeptidase CCP1 in human cINs reduces microtubule glutamylation and doublecortin recruitment, thereby facilitating leading-process branching. These findings identify a CCP1-dependent mechanism regulating cIN dispersion and suggest that evolutionary changes in cIN migration contribute to divergent patterns of cortical morphogenesis across mammals.

neuroscience↗

bioRxiv2025

DTX4 regulates neural progenitor transitions during cortical development

Neural progenitors drive cellular diversification in the neocortex. Prolongation of their proliferative capacity and increased diversity underpins the evolutionary expansion and morphological complexity of the human neocortex. Here, we investigate the mechanisms that regulate maintenance of the highly proliferative early neural progenitor subtypes and transition to subsequent progenitors of limited proliferative capacity during human and murine neocortical development. We identify DTX4, a Deltex family member, as an evolutionarily conserved molecular determinant of neural progenitor identity in the mammalian neocortex. DTX4 sustains the identity of radial glia, a highly proliferative progenitor subtype. Loss of DTX4, on the other hand, is a prerequisite for the generation of intermediate progenitors which possess low proliferative capacity. Perturbing DTX4 expression in human cerebral organoids and in the murine neocortex, alters progenitor composition, thereby inducing changes in neuronal diversity and cortical morphology. Mechanistically, we reveal that DTX4 controls progenitor identity by regulating the length of the cell cycle. Our findings underscore the critical role of cell cycle dynamics and of DTX4 in determining progenitor identity and thereby defining neuronal outcome during mammalian development. Highlights[bullet] The Deltex family member, DTX4, is expressed in human and murine neuroepithelia and radial glial progenitors but is absent in intermediate progenitor cells. [bullet]DTX4 maintains radial glia identity and prevents generation of intermediate progenitors during murine and human development. [bullet]Disruption of DTX4 expression compromises neuronal composition and neocortical architecture [bullet]DTX4 regulates progenitor identity by regulating cell cycle length

neuroscience↗