Neurogenesis in the developing human cerebral cortex occurs at a particularly slow rate owing in part to cortical neural progenitors preserving their progenitor state for a relatively long time, while generating neurons. How this balance between the progenitor and neurogenic state is regulated, and whether it contributes to species-specific brain temporal patterning, is poorly understood. Here, we show that the characteristic potential of human neural progenitor cells (NPCs) to remain in a progenitor state as they generate neurons for a prolonged amount of time requires the amyloid precursor protein (APP). In contrast, APP is dispensable in mouse NPCs, which undergo neurogenesis at a much faster rate. Mechanistically, APP cell-autonomously contributes to protracted neurogenesis through suppression of the proneurogenic activator protein–1 transcription factor and facilitation of canonical WNT signaling. We propose that the fine balance between self-renewal and differentiation is homeostatically regulated by APP, which may contribute to human-specific temporal patterns of neurogenesis.

The human neocortex has undergone significant expansion during evolution partially underlying increased human cognitive capacities. The 16 billion neurons of the human neocortex are derived from a limited number of cortical neural progenitor cells (NPCs). Human cortical NPCs initially generate neurons at a slow rate while preserving their progenitor state for a prolonged period, partly contributing to increased human cortical size. How the balance between the progenitor state and neurogenic state is regulated, and whether it contributes to species-specific brain patterning, is poorly understood. We find that the human Amyloid Precursor Protein (APP), whose mutations cause Alzheimers disease, specifically regulates this fine balance. Mechanistically, APP regulates these two aspects via two pathways: the AP1 transcription factor and the canonical Wnt pathway. We propose that APP is a homeostatic regulator of the neurogenic potential of cortical NPCs thus potentially contributing to human-specific patterns of neurogenesis.