大脑皮层通过一系列精心策划的细胞和分子事件发展，最终产生高度特化的神经元和胶质细胞。在发育过程中，皮层神经元和胶质获得精确的细胞排列和结构，以支持更高级的认知功能。几十年的研究使用啮齿动物模型、自然回脑动物模型、人类病理标本以及最近的人类脑器官模型揭示，啮齿动物重现了人类大脑皮层的一些但不是全部的细胞和分子特征。而啮齿动物的大脑皮层是光滑的或无脑沟的，更大的哺乳动物，包括人类和非人灵长类，具有高度褶皱/回脑皮层，以适应神经元质量的扩展和表面积的增加。一些基因进化出来，用于推动皮质脑沟化，这些基因是通过基因复制或新生产生的，或是通过改变祖先基因或其基因调控区域的结构/功能产生的。主要的脑沟在特定的位置形成，受几个信号通路（如Notch、Fgf、Wnt、PI3K、Shh）的分子"蓝图"的预设，并受胞外基质的影响。影响神经前体细胞增殖和/或神经发生的突变，主要是上层神经元的突变，会扰乱脑沟化过程。下面我们将回顾皮质折叠的分子驱动因素及其在疾病中的作用。

The cerebral cortex develops through a carefully conscripted series of cellular and molecular events that culminate in the production of highly specialized neuronal and glial cells. During development, cortical neurons and glia acquire a precise cellular arrangement and architecture to support higher-order cognitive functioning. Decades of study using rodent models, naturally gyrencephalic animal models, human pathology specimens, and, recently, human cerebral organoids, reveal that rodents recapitulate some but not all the cellular and molecular features of human cortices. Whereas rodent cortices are smooth-surfaced or lissencephalic, larger mammals, including humans and nonhuman primates, have highly folded/gyrencephalic cortices that accommodate an expansion in neuronal mass and increase in surface area. Several genes have evolved to drive cortical gyrification, arising from gene duplications or de novo origins, or by alterations to the structure/function of ancestral genes or their gene regulatory regions. Primary cortical folds arise in stereotypical locations, prefigured by a molecular "blueprint" that is set up by several signaling pathways (e.g., Notch, Fgf, Wnt, PI3K, Shh) and influenced by the extracellular matrix. Mutations that affect neural progenitor cell proliferation and/or neurogenesis, predominantly of upper-layer neurons, perturb cortical gyrification. Below we review the molecular drivers of cortical folding and their roles in disease.