Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder.
Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder.
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DOI：
10.1186/s13229-023-00540-x
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发表时间：
2023-02-20
期刊：
影响因子：
6.2
通讯作者：
中科院分区：
文献类型：
--
作者：
通过杂合基因缺失或功能缺失变体破坏18q12.3上的SETBP 1（SET结合蛋白1）导致SETBP 1紊乱。临床特征通常与中度至重度智力残疾、自闭症特征以及言语和运动延迟相关。尽管SETBP 1与神经发育障碍有关，但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，我们在人胚胎干细胞（hESC）中生成了一个SETBP 1缺失模型，并使用一系列细胞测定，全基因组转录组分析和基于药物的表型拯救来检查SETBP 1缺陷对神经祖细胞（NPC）和来自这些干细胞的神经元的影响。神经诱导有效地发生在所有的SETBP 1删除模型所示的均匀过渡到神经roximity。然而，SETBP 1缺陷型NPC表现出延长的增殖窗口和神经发生减少，同时缺乏获得腹侧前脑命运的能力。全基因组转录组分析和蛋白质生化分析显示，在SETBP 1缺失的细胞中，Wnt/β-连环蛋白信号转导的激活增强。重要的是，用小分子Wnt抑制剂XAV 939处理SETBP 1缺陷型NPC恢复了超经典β-连环蛋白活性，并恢复了皮质和MGE神经元分化。目前的研究是基于对基因组编辑的SETBP 1缺失的同基因hESC系的分析，进一步的研究将受益于使用患者来源的iPSC系，这些iPSC系可能具有加重SETBP 1疾病脑病理学的额外遗传风险。我们确定了SETBP 1在控制前脑祖细胞扩增和神经源性分化中的重要作用。我们的研究在人类皮层神经发生过程中建立了SETBP 1和Wnt/β-catenin信号之间的新的调节联系，并为SETBP 1疾病的结构异常和潜在的治疗途径提供了机制见解。在线版本包含补充材料，可通过10.1186/s13229-023-00540-x获得。
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. The online version contains supplementary material available at 10.1186/s13229-023-00540-x.
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