SETBP1 紊乱的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。

IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Molecular Autism Pub Date : 2023-02-20 DOI:10.1186/s13229-023-00540-x
Lucia F Cardo, Daniel C de la Fuente, Meng Li
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引用次数: 0

摘要

背景:18q12.3上的SETBP1(SET结合蛋白1)因杂合子基因缺失或功能缺失变异而导致紊乱。临床特征通常与中度至重度智力障碍、自闭症特征以及语言和运动迟缓有关。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:方法:我们利用CRISPR/Cas9基因组编辑技术,在人类胚胎干细胞(hESCs)中生成了SETBP1缺失模型,并通过一系列细胞检测、全基因组转录组分析和基于药物的表型拯救,研究了SETBP1缺失对神经祖细胞(NPCs)和神经元的影响:结果:在所有SETBP1缺失模型中,神经诱导都能有效地发生,这表现为神经细胞均匀地过渡到神经莲座。然而,SETBP1缺失的NPCs表现出增殖窗口期延长、神经发生减少以及获得腹侧前脑命运的能力不足。全基因组转录组分析和蛋白质生化分析表明,在 SETBP1 缺失的细胞中,Wnt/β-catenin 信号激活增强。最重要的是,用小分子Wnt抑制剂XAV939处理SETBP1缺失的NPC,可恢复超典型β-catenin活性,并恢复皮质和MGE神经元分化:目前的研究基于对基因组编辑SETBP1缺失的同源hESC系的分析,进一步的研究将受益于使用患者衍生的iPSC系,这些iPSC系可能携带额外的遗传风险,从而加重SETBP1紊乱的脑病理学:我们发现了 SETBP1 在控制前脑祖细胞扩增和神经原分化中的重要作用。我们的研究在人类大脑皮层神经发生过程中建立了 SETBP1 与 Wnt/β-catenin 信号之间的新型调控联系,并为 SETBP1 障碍的结构异常和潜在治疗途径提供了机制性见解。
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Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder.

Background: 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.

Methods: 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.

Results: 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.

Limitations: 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.

Conclusions: 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.

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来源期刊
Molecular Autism
Molecular Autism GENETICS & HEREDITY-NEUROSCIENCES
CiteScore
12.10
自引率
1.60%
发文量
44
审稿时长
17 weeks
期刊介绍: Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.
期刊最新文献
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