OBJECTIVE Neural tube defects (NTDs) are the most serious and common birth defects in the clinic. The SRY-related HMG box B1 (SoxB1) gene family has been implicated in different processes of early embryogenesis. Sox19b is a maternally expressed gene in the SoxB1 family that is found in the region of the presumptive central nervous system (CNS), but its role and mechanism in embryonic neural stem cells (NSCs) during neural tube development have not yet been explored. Considering that Sox19b is specific to bony fish, we intended to investigate the role and mechanism of Sox19b in neural tube development in zebrafish embryos. MATERIAL AND METHODS Morpholino (MO) antisense oligonucleotides were used to construct a Sox19b loss-of-function zebrafish model. The phenotype and the expression of related genes were analysed by in situ hybridization and immunolabelling. Epigenetic modifications were detected by western blot and chromatin immunoprecipitation. RESULTS In this study, we found that zebrafish embryos exhibited a reduced or even deleted forebrain phenotype after the expression of the Sox19b gene was inhibited. Moreover, we found for the first time that knockdown of Sox19b reduced the proliferation of NSCs; increased the transcription levels of Ngn1, Ascl1, HuC, Islet1, and cyclin-dependent kinase (CDK) inhibitors; and led to premature differentiation of NSCs. Finally, we found that knockdown of Sox19b decreased the levels of EZH2/H3K27me3 and decreased the level of H3K27me3 at the promoters of Ngn1 and ascl1a. CONCLUSION Together, our data demonstrate that Sox19b plays an essential role in early NSC proliferation and differentiation through EZH2-mediated histone methylation in neural tube development. This study established the role of transcription factor Sox19b and epigenetic factor EZH2 regulatory network on NSC development, which provides new clues and theoretical guidance for the clinical treatment of neural tube defects.

中文翻译：

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SOX19b通过斑马鱼神经管发育中的EZH2介导的组蛋白甲基化调节神经干细胞的过早神经元分化。

目的神经管缺损（NTD）是临床上最严重，最常见的出生缺陷。SRY相关的HMG盒B1（SoxB1）基因家族已牵涉到早期胚胎发生的不同过程。Sox19b是在SoxB1家族中由母体表达的基因，位于假定的中枢神经系统（CNS）区域，但尚未探索其在神经管发育过程中在胚胎神经干细胞（NSCs）中的作用和机制。考虑到Sox19b特定于骨鱼，我们打算研究Sox19b在斑马鱼胚胎神经管发育中的作用和机制。材料与方法Morpholino（MO）反义寡核苷酸用于构建Sox19b功能丧失的斑马鱼模型。通过原位杂交和免疫标记分析表型和相关基因的表达。通过Western印迹和染色质免疫沉淀检测表观遗传修饰。结果在这项研究中，我们发现抑制Sox19b基因的表达后，斑马鱼胚胎表现出减少或什至删除的前脑表型。此外，我们首次发现敲除Sox19b可以减少NSC的增殖。增加Ngn1，Ascl1，HuC，Islet1和细胞周期蛋白依赖性激酶（CDK）抑制剂的转录水平；并导致NSC的过早分化。最后，我们发现敲除Sox19b可以降低Ngn1和ascl1a启动子的EZH2 / H3K27me3水平，并降低H3K27me3水平。结论在一起 我们的数据表明，Sox19b通过EZH2介导的组蛋白甲基化在神经管发育中在早期NSC增殖和分化中起重要作用。本研究建立了转录因子Sox19b和表观遗传因子EZH2调节网络在神经干细胞发展中的作用，为神经管缺陷的临床治疗提供了新的线索和理论指导。