Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Rev Genet. 2024 Jan;25(1):26-45. doi: 10.1038/s41576-023-00626-5. Epub 2023 Jul 28.
Brain development in humans is achieved through precise spatiotemporal genetic control, the mechanisms of which remain largely elusive. Recently, integration of technological advances in human stem cell-based modelling with genome editing has emerged as a powerful platform to establish causative links between genotypes and phenotypes directly in the human system. Here, we review our current knowledge of complex genetic regulation of each key step of human brain development through the lens of evolutionary specialization and neurodevelopmental disorders and highlight the use of human stem cell-derived 2D cultures and 3D brain organoids to investigate human-enriched features and disease mechanisms. We also discuss opportunities and challenges of integrating new technologies to reveal the genetic architecture of human brain development and disorders.
人类大脑的发育是通过精确的时空遗传控制来实现的，其机制在很大程度上仍难以捉摸。最近，在人类基于干细胞的建模技术与基因组编辑的整合方面取得了进展，这为在人类系统中直接建立基因型与表型之间的因果关系提供了一个强大的平台。在这里，我们通过进化特化和神经发育障碍的视角来回顾人类大脑发育的每个关键步骤的复杂遗传调控的现有知识，并强调使用人类干细胞衍生的 2D 培养物和 3D 类脑器官来研究人类丰富的特征和疾病机制。我们还讨论了整合新技术的机会和挑战，以揭示人类大脑发育和疾病的遗传结构。
