title: Deltex1 is inhibited by the Notch-Hairy/E(Spl) signaling pathway and induces neuronal and glial differentiation.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1 Road, Taoyuan, 33383, Taiwan. yccheng@mail.cgu.edu.tw.|Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan. yccheng@mail.cgu.edu.tw.
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, Chang Gung Memorial Hospital, Chiayi branch, Chiayi, Taiwan.|College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yin-Cheng
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan.|College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan.
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1 Road, Taoyuan, 33383, Taiwan.
authors.forename: Hung-Yu
authors.initials: HY
authors.lastname: Shih
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1 Road, Taoyuan, 33383, Taiwan.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1 Road, Taoyuan, 33383, Taiwan.
authors.forename: Sheng-Jia
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan.
authors.forename: Ching-Chi
authors.initials: CC
authors.lastname: Chiu
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1 Road, Taoyuan, 33383, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Huang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Yun-Jin
authors.initials: YJ
authors.lastname: Jiang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055495:Neurogenesis / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051880:Receptors, Notch; D029961:Zebrafish Proteins; C579678:deltex protein 1, zebrafish