Reaping what you grow: rethinking apoptosis in cortical folding

Cortical folding is a defining feature of mammalian brain evolution widely attributed to spatially patterned cell proliferation, neuronal differentiation, and migration that drive regional expansion of the cerebral cortex. Growth-centric models have dominated theories of gyrification for decades; however, cortical morphogenesis is not governed by expansion alone. In this hypothesis-driven review, we reconceptualize cell death as a potential driver of cortical folding. We synthesize evidence indicating that apoptosis is spatiotemporally regulated during healthy brain development, influences cortical size and structure when perturbed, and functions differently in cell type- and layer-specific contexts. Apoptosis has been largely overlooked as an instructive contributor to gyral and sulcal formation. We explore the possibility that spatially patterned apoptosis may directly modulate cell density, radial units, and cortical topology, acting in concert with, rather than a consequence of, proliferation and migration to sculpt the developing brain. We propose that this is a substantial area of investigation given the limited data on spatially patterned apoptosis and gyrification and the evidence that would be required to substantiate this hypothesis. Recognizing the potential for apoptosis as a candidate driver of gyrification expands current developmental models and provides a new testable framework for interpreting both evolutionary cortical expansion and malformations.