Abstract
ObjectiveNeural 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 methodsMorpholino (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.ResultsIn 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.ConclusionTogether, 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.
Highlights
The embryonic neural tube is the precursor of the central nervous system
We found for the first time that knockdown of Sox19b reduced the proliferation of neural stem cells (NSCs); increased the transcription levels of Ngn1, Ascl1, HuC, Islet1, and cyclindependent kinase (CDK) inhibitors; and led to premature differentiation of NSCs
In combination with previous reports and our results, the expression characteristics of the SRY-related HMG box B1 (SoxB1) family in zebrafish are as follows: only Sox19b was highly expressed during the maternal phase, Sox3 and Sox19a were expressed initially in the 1000 cell phase, and Sox2 was expressed at the beginning of the 30% epiboly phase
Summary
Neural tube development is a continuous development process from the appearance of the nerve plate to the closure of the nerve tube [1]. In this process, congenital neurodevelopmental diseases caused by neural tube formation and closure disorder are called neural tube defects (NTDs) [2, 3]. NTDs are the most serious and common birth defects in clinical practice and are the main causes of disability and death in newborns [4, 5]. The clinical manifestations of NTDs include brain deformity, cerebral dysplasia, encephalocele, spina bifida, and spinal meningocele [6,7,8]. The molecular mechanisms of NTDs are not yet fully understood
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