Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite the association of SETBP1 with neurodevelopmental disorders, little is known about its role in brain development. Using CRISPR/Cas9 genome editing technology, we generated a SETBP1 deletion model in human embryonic stem cells (hESCs) and examined the effects of SETBP1-deficiency in neural progenitors (NPCs) and neurons derived from these stem cells using a battery of cellular assays, genome-wide transcriptomic profiling and drug-based phenotypic rescue. Neural induction occurred efficiently in all SETBP1 deletion models as indicated by uniform transition into neural rosettes. However, SETBP1-deficient NPCs exhibited an extended proliferative window and a decrease in neurogenesis coupled with a deficiency in their ability to acquire ventral forebrain fate. Genome-wide transcriptome profiling and protein biochemical analysis revealed enhanced activation of Wnt/β-catenin signaling in SETBP1 deleted cells. Crucially, treatment of the SETBP1-deficient NPCs with a small molecule Wnt inhibitor XAV939 restored hyper canonical β-catenin activity and restored both cortical and MGE neuronal differentiation. The current study is based on analysis of isogenic hESC lines with genome-edited SETBP1 deletion and further studies would benefit from the use of patient-derived iPSC lines that may harbor additional genetic risk that aggravate brain pathology of SETBP1 disorder. We identified an important role for SETBP1 in controlling forebrain progenitor expansion and neurogenic differentiation. Our study establishes a novel regulatory link between SETBP1 and Wnt/β-catenin signaling during human cortical neurogenesis and provides mechanistic insights into structural abnormalities and potential therapeutic avenues for SETBP1 disorder.

中文翻译：

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SETBP1 疾病人类干细胞模型中受损的神经发生和神经祖细胞命运选择

18q12.3 上的 SETBP1（SET 结合蛋白 1）因杂合基因缺失或功能丧失变异而中断会导致 SETBP1 紊乱。临床特征通常与中度至重度智力障碍、自闭症特征以及言语和运动迟缓有关。尽管 SETBP1 与神经发育障碍有关，但人们对其在大脑发育中的作用知之甚少。使用 CRISPR/Cas9 基因组编辑技术，我们在人类胚胎干细胞 (hESC) 中生成了 SETBP1 缺失模型，并使用一系列细胞检测方法检查了 SETBP1 缺陷对神经祖细胞 (NPC) 和源自这些干细胞的神经元的影响，全基因组转录组学分析和基于药物的表型拯救。神经诱导在所有 SETBP1 缺失模型中有效发生，如均匀过渡到神经玫瑰花结所示。然而，缺乏 SETBP1 的 NPC 表现出延长的增殖窗口和神经发生的减少，以及它们获得腹侧前脑命运的能力的缺陷。全基因组转录组分析和蛋白质生化分析揭示了 SETBP1 缺失细胞中 Wnt/β-catenin 信号通路的增强激活。至关重要的是，用小分子 Wnt 抑制剂 XAV939 治疗 SETBP1 缺陷的 NPC 可恢复超典型的 β-连环蛋白活性并恢复皮质和 MGE 神经元分化。目前的研究基于对具有基因组编辑的 SETBP1 缺失的同基因 hESC 系的分析，进一步的研究将受益于使用源自患者的 iPSC 系，这些 iPSC 系可能具有额外的遗传风险，会加重 SETBP1 疾病的脑病理学。我们确定了 SETBP1 在控制前脑祖细胞扩张和神经源性分化中的重要作用。我们的研究在人类皮质神经发生过程中建立了 SETBP1 和 Wnt/β-catenin 信号之间的新型调节联系，并提供了对结构异常和 SETBP1 疾病潜在治疗途径的机制见解。