开发需要CTCF组织的三维基因组结构。临床上发现的 CTCF 突变与不良发育结果有关。然而，潜在的机制仍然难以捉摸。在这项研究中，我们通过将这种突变引入小鼠模型和人胚胎干细胞衍生的皮质类器官模型中，探讨了位于 CTCF 第 11 锌指内的临床相关 R567W 点突变的调节作用。具有纯合 CTCFR567W 突变的小鼠表现出生长障碍，导致出生后死亡，并且在病理和单细胞转录组水平上脑、心脏和肺发育出现偏差。这种突变会导致干细胞样细胞过早衰竭，加速 GABA 能神经元的成熟，并破坏神经发育和突触通路。此外，它还特异性阻碍 CTCF 与核心共有位点上游的外围基序结合，导致局部染色质结构和基因表达的改变，特别是在聚集的原钙粘蛋白位点。使用人类皮质类器官的比较分析反映了这种突变引起的后果。总之，这项研究阐明了 CTCFR567W 突变对人类神经发育障碍的影响，为潜在的治疗干预铺平了道路。© 2024。作者。

The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.© 2024. The Author(s).