Abstract
BackgroundNotch signaling has been conserved throughout evolution and plays a fundamental role in various neural developmental processes and the pathogenesis of several human cancers and genetic disorders. However, how Notch signaling regulates various cellular processes remains unclear. Although Deltex proteins have been identified as cytoplasmic downstream elements of the Notch signaling pathway, few studies have been reported on their physiological role.ResultsWe isolated zebrafish deltex1 (dtx1) and showed that this gene is primarily transcribed in the developing nervous system, and its spatiotemporal expression pattern suggests a role in neural differentiation. The transcription of dtx1 was suppressed by the direct binding of the Notch downstream transcription factors Her2 and Her8a. Overexpressing the complete coding sequence of Dtx1 was necessary for inducing neuronal and glial differentiation. By contrast, disrupting Dtx1 expression by using a Dtx1 construct without the RING finger domain reduced neuronal and glial differentiation. This effect was phenocopied by the knockdown of endogenous Dtx1 expression by using morpholinos, demonstrating the essential function of the RING finger domain and confirming the knockdown specificity. Cell proliferation and apoptosis were unaltered in Dtx1-overexpressed and -deficient zebrafish embryos. Examination of the expression of her2 and her8a in embryos with altered Dtx1 expression showed that Dxt1-induced neuronal differentiation did not require a regulatory effect on the Notch–Hairy/E(Spl) pathway. However, both Dtx1 and Notch activation induced glial differentiation, and Dtx1 and Notch activation negatively inhibited each other in a reciprocal manner, which achieves a proper balance for the expression of Dtx1 and Notch to facilitate glial differentiation. We further confirmed that the Dtx1–Notch–Hairy/E(Spl) cascade was sufficient to induce neuronal and glial differentiation by concomitant injection of an active form of Notch with dtx1, which rescued the neuronogenic and gliogenic defects caused by the activation of Notch signaling.ConclusionsOur results demonstrated that Dtx1 is regulated by Notch–Hairy/E(Spl) signaling and is a major factor specifically regulating neural differentiation. Thus, our results provide new insights into the mediation of neural development by the Notch signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-015-0055-5) contains supplementary material, which is available to authorized users.
Highlights
Notch signaling has been conserved throughout evolution and plays a fundamental role in various neural developmental processes and the pathogenesis of several human cancers and genetic disorders
Cells with different dtx1 expression levels spanned the entire central nervous system, Fig. 1 dtx1 expression in developing zebrafish. dtx1 expression was detected using in situ hybridization in the developing nervous system during zebrafish embryogenesis
To examine whether Dtx1 reciprocally regulates Notch signaling in neuronal differentiation, we examined the expression of her2 and her8a in embryos with dtx1 gain- and loss-of function at different developmental stages
Summary
Notch signaling has been conserved throughout evolution and plays a fundamental role in various neural developmental processes and the pathogenesis of several human cancers and genetic disorders. In the developing central nervous system, neural progenitor cells in the ventricular zone of the neural tube proliferate extensively and, following asymmetric cell division, generate neuronal and glial precursors that produce various types of neurons and glial cells. Generating these neural cells requires numerous gene regulatory and signaling processes, and understanding the regulatory mechanisms during development may provide crucial implications for developing repair therapies for treating nervous system injuries and tumors. This interaction triggers cleavage to release a cytoplasmic fragment of Notch that enters the nucleus and interacts with the DNA-binding protein CSL (CBF/RBP-J, Su(H), LAG-1/CSL), leading to the transcription of target genes such as Hairy and Enhancer-of-split [Hairy/E(spl)] [3]
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