The human brain is characterized by the large size and intricate folding of its cerebral cortex, which are fundamental for our higher cognitive function and frequently altered in pathological dysfunction. Cortex folding is not unique to humans, nor even to primates, but is common across mammals. Cortical growth and folding are the result of complex developmental processes that involve neural stem and progenitor cells and their cellular lineages, the migration and differentiation of neurons, and the genetic programs that regulate and fine-tune these processes. All these factors combined generate mechanical stress and strain on the developing neural tissue, which ultimately drives orderly cortical deformation and folding. In this review we examine and summarize the current knowledge on the molecular, cellular, histogenic and mechanical mechanisms that are involved in and influence folding of the cerebral cortex, and how they emerged and changed during mammalian evolution. We discuss the main types of pathological malformations of human cortex folding, their specific developmental origin, and how investigating their genetic causes has illuminated our understanding of key events involved. We close our review by presenting the state-of-the-art animal and in vitro models of cortex folding that are currently used to study these devastating developmental brain disorders in children, and what are the main challenges that remain ahead of us to fully understand brain folding.

中文翻译：

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折叠大脑：从发育到疾病建模

人脑的特点是其大脑皮层体积大且折叠复杂，这是我们更高认知功能的基础，并且经常在病理功能障碍中改变。皮层折叠不是人类独有的，甚至灵长类动物也不是，而是在哺乳动物中很常见。皮层生长和折叠是复杂发育过程的结果，这些过程涉及神经干细胞和祖细胞及其细胞谱系、神经元的迁移和分化，以及调节和微调这些过程的遗传程序。所有这些因素结合起来会对发育中的神经组织产生机械应力和应变，最终驱动皮质变形和折叠。在这篇综述中，我们检查并总结了当前关于分子、细胞、参与和影响大脑皮层折叠的组织发生和机械机制，以及它们在哺乳动物进化过程中如何出现和变化。我们讨论了人类皮质折叠病理性畸形的主要类型、它们的特定发育起源，以及调查它们的遗传原因如何阐明我们对所涉及的关键事件的理解。我们通过展示目前用于研究儿童这些破坏性发育性脑部疾病的最先进的动物和体外皮质折叠模型来结束我们的审查，以及我们要充分理解的主要挑战是什么大脑折叠。我们讨论了人类皮质折叠病理性畸形的主要类型、它们的特定发育起源，以及调查它们的遗传原因如何阐明我们对所涉及的关键事件的理解。我们通过展示目前用于研究儿童这些破坏性发育性脑部疾病的最先进的动物和体外皮质折叠模型来结束我们的审查，以及我们要充分理解的主要挑战是什么大脑折叠。我们讨论了人类皮质折叠病理性畸形的主要类型、它们的特定发育起源，以及调查它们的遗传原因如何阐明我们对所涉及的关键事件的理解。我们通过展示目前用于研究儿童这些破坏性发育性脑部疾病的最先进的动物和体外皮质折叠模型来结束我们的审查，以及我们要充分理解的主要挑战是什么大脑折叠。