NOTCH2NLB is a human-specific protein that promotes neural progenitor proliferation and contributes to the evolutionary expansion of the human neocortex by enhancing Notch signaling through dual mechanisms. In apical progenitors, NOTCH2NLB drives proliferation and self-renewal of the apical progenitor pool 1. At the molecular level, it enhances Notch signaling both non-cell-autonomously via direct interaction with NOTCH2 receptors and cell-autonomously by inhibiting cis Delta/Notch interactions that would otherwise promote neuronal differentiation 23. This delayed differentiation ultimately increases overall neuronal production. When coexpressed with the related human-specific gene NBPF14, NOTCH2NLB orchestrates coordinated expansion of basal progenitor populations while maintaining apical progenitor self-renewal, a combination essential for neocortical expansion 1. Recent evolutionary analysis reveals ongoing adaptive evolution of NOTCH2NL genes toward reduced protein dosage in modern humans, suggesting the optimal dosage remains unsettled in the population 4. Disease-associated copy-number variations at the 1q21.1 locus encompassing NOTCH2NLB are linked to neurodevelopmental disorders, with duplications associated with macrocephaly and autism spectrum disorder, and deletions with microcephaly and schizophrenia 2.