Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France.
Cell Rep. 2023 Aug 29;42(8):112845. doi: 10.1016/j.celrep.2023.112845. Epub 2023 Jul 21.
Protocadherins (PCDHs) are cell adhesion molecules that regulate many essential neurodevelopmental processes related to neuronal maturation, dendritic arbor formation, axon pathfinding, and synaptic plasticity. Biallelic loss-of-function variants in PCDH12 are associated with several neurodevelopmental disorders (NDDs). Despite the highly deleterious outcome resulting from loss of PCDH12, little is known about its role during brain development and disease. Here, we show that PCDH12 loss severely impairs cerebral organoid development, with reduced proliferative areas and disrupted laminar organization. 2D models further show that neural progenitor cells lacking PCDH12 prematurely exit the cell cycle and differentiate earlier when compared with wild type. Furthermore, we show that PCDH12 regulates neuronal migration and suggest that this could be through a mechanism requiring ADAM10-mediated ectodomain shedding and/or membrane recruitment of cytoskeleton regulators. Our results demonstrate a critical involvement of PCDH12 in cortical organoid development, suggesting a potential cause for the pathogenic mechanisms underlying PCDH12-related NDDs.
原钙黏蛋白（protocadherins，PCDHs）是细胞黏附分子，可调节多种与神经元成熟、树突分支形成、轴突寻路和突触可塑性相关的重要神经发育过程。PCDH12 的双等位基因功能丧失变异与多种神经发育障碍（neurodevelopmental disorders，NDDs）有关。尽管 PCDH12 的缺失会导致高度有害的后果，但人们对其在大脑发育和疾病中的作用知之甚少。在这里，我们发现 PCDH12 的缺失严重损害了大脑类器官的发育，导致增殖区域减少和层状组织紊乱。二维模型进一步表明，与野生型相比，缺乏 PCDH12 的神经祖细胞更早地退出细胞周期并更早分化。此外，我们还发现 PCDH12 调节神经元迁移，并提示这可能是通过一种需要 ADAM10 介导的细胞外结构域脱落和/或细胞骨架调节因子的膜募集的机制。我们的研究结果表明 PCDH12 对皮质类器官发育有重要影响，提示 PCDH12 相关 NDD 潜在的致病机制。
