title: The transcription factor hairy/E(spl)-related 2 induces proliferation of neural progenitors and regulates neurogenesis and gliogenesis.
abstract: The study of molecular regulation in neural development provides information to understand how diverse neural cells are generated. It also helps to establish therapeutic strategies for the treatment of neural degenerative disorders and brain tumors. The Hairy/E(spl) family members are potential targets of Notch signaling, which is fundamental to neural cell maintenance, cell fate decisions, and compartment boundary formation. In this study, we isolated a zebrafish homolog of Hairy/E(spl), her2, and showed that this gene is expressed in neural progenitor cells and in the developing nervous system. The expression of her2 required Notch activation, as revealed by a Notch-defective mutant and a chemical inhibitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The endogenous expression of Her2 was altered by both overexpression and morpholino-knockdown approaches, and the results demonstrated that Her2 was both necessary and sufficient to promote the proliferation of neural progenitors by inhibiting the transcription of the cell cycle inhibitors cdkn1a, cdkn1ba, and cdkn1bb. Her2 knockdown caused premature neuronal differentiation, which indicates that Her2 is essential for inhibiting neuronal differentiation. At a later stage of neural development, Her2 could induce glial differentiation. The overexpression of Her2 constructs lacking the bHLH or WRPW domain phenocopied the effect of the morpholino knockdown, demonstrating the essential function of these two domains and further confirming the knockdown specificity. In conclusion, our data reveal that Her2 promotes progenitor proliferation and maintains progenitor characteristics by inhibiting neuronal differentiation. Together, these two mechanisms ensure the proper development of the neural progenitor cell pool.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1st Road, Taoyuan 33383, Taiwan. Electronic address: yccheng@mail.cgu.edu.tw.
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Department of Life Science, Fu Jen Catholic University, New Taipei City 242, Taiwan.
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1st 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 1st Road, Taoyuan 33383, Taiwan.
authors.forename: Tsu-Lin
authors.initials: TL
authors.lastname: Ma
authors.affiliation: Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.affiliation: Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yin-Cheng
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, 259 Wen-Hwa 1st 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 1st Road, Taoyuan 33383, Taiwan.
authors.forename: Sheng-Jia
authors.initials: SJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D004151:Dipeptides / Q000737:chemistry; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D004151:Dipeptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D029961:Zebrafish Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
keywords: Glial differentiation; Hairy/E(spl)-related 2; Neural progenitor cells; Neuronal differentiation; Zebrafish