Opposing actions of histone deacetylase 1 and Notch signalling restrict expression of erm and fgf20a to hindbrain rhombomere centres during zebrafish neurogenesis
MRC Centre for Developmental and Biomedical Genetics, Department of Biomedical Science, University of Sheffield, Sheffield, UK.The International journal of developmental biology (Impact Factor: 1.9). 01/2011; 55(6):597-602. DOI: 10.1387/ijdb.113315el
The rate and pattern of neurogenesis in the developing vertebrate nervous system is controlled by a complex interplay of intercellular signalling pathways and transcriptional control mechanisms. In the zebrafish hindbrain, Fgf20a promotes transcription of the gene encoding the ETS-domain transcription factor Erm in the non-neurogenic centres of rhombomeres. Here, we demonstrate that the epigenetic regulator, Histone Deacetylase 1 (Hdac1) and the Notch signalling pathway have opposing functions in regulating expression of both erm and fgf20a in the zebrafish hindbrain. Our results show that Hdac1 is required for expression of erm and fgf20a in rhombomeres, and that the Hdac1-dependent expression of these two genes is attenuated in rhombomere boundary regions by Notch signalling activity, thereby restricting erm and fgf20a transcripts to narrow stripes of cells at rhombomere centres.
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ABSTRACT: The posterior lateral line (PLL) system in zebrafish has recently become a model for investigating tissue morphogenesis. PLL primordium periodically deposits neuromasts as it migrates along the horizontal myoseptum from head to tail of the embryonic fish, and this migration requires activity of various molecular mechanisms. Histone deacetylases (HDACs) have been implicated in numerous biological processes of development, by regulating gene transcription, but their roles in regulating PLL during embryonic development have up to now remained unexplored. In this study, we used HDAC inhibitors to investigate the role of HDACs in early development of the zebrafish PLL sensory system. We further investigated development of the PLL by cell-specific immunostaining and in situ hybridization. Our analysis showed that HDACs were involved in zebrafish PLL development as pharmacological inhibition of HDACs resulted in its defective formation. We observed that migration of PLL primordium was altered and accompanied by disrupted development of PLL neuromasts in HDAC inhibitor-treated embryos. In these, positions of PLL neuromasts were affected. In particular, the first PLL neuromast was displaced posteriorly in a treatment dose-dependent manner. Primordium cell proliferation was reduced upon HDAC inhibition. Finally, we showed that inhibition of HDAC function reduced numbers of hair cells in PLL neuromasts of HDAC inhibitor-treated embryos. Here, we have revealed a novel role for HDACs in orchestrating PLL morphogenesis. Our results suggest that HDAC activity is necessary for control of cell proliferation and migration of PLL primordium and hair cell differentiation during early stages of PLL development in zebrafish.Cell Proliferation 11/2013; 47(1). DOI:10.1111/cpr.12081 · 3.12 Impact Factor
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ABSTRACT: Radiotherapy is often employed for treatment of head and neck cancer. Unfortunately, its neurotoxic effects on normal brain tissue often compromise the quality of life (QOL) for survivors. Particularly, acute cognitive deficit (ACD), which can occur several days to one month after irradiation, limits its therapeutic use. Impairment of neurogenesis in the hippocampus plays a key role in development of radiation-induced cognitive deficit, and brain-derived neurotrophic factor (BDNF) may be involved. In the present study, we re-evaluated the effects of different doses of radiation on development of ACD in Sprague Dawley rats. Our results showed that 30 Gy, but not 2 Gy or 10 Gy of whole brain radiation (WBI), led to significant deficits cognitive functions at one month post-irradiation. At 7 and 30 days post irradiation, immunofluorescence showed WBI had seriously impeded the production of new neurons and shortened their survival time. Additionally, decreased bdnf mRNA and protein expression were also observed. A significant decrease in histone deacetylase 1 (HDAC1)-dependent H3 acetylation was observed at bdnf promoters by ChIP analysis. TSA, an HDAC inhibitor, triggered bdnf transcription and rescued neurogenesis impairment following WBI. In summary, our results suggest that a single-dose exposure to 30 Gy WBI induced acute cognitive dysfunction in rats. Additionally, radiation-induced persistent inhibition of bdnf gene transcription resulting from lowered rates of HDAC1-dependent H3 acetylation was associated with long-term impairment of neurogenesis in the denate gyrus (DG). Triggering of BDNF-TrkB signaling by inhibition of HDAC-1 may be used to stimulate neurogenesis.Brain Research 08/2014; 1577. DOI:10.1016/j.brainres.2014.06.035 · 2.84 Impact Factor
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ABSTRACT: Background: Valproic acid (VPA) has been used to treat epilepsy and bipolar disorder. Several reports have demonstrated that VPA functions as a histone deacetylase (HDAC) inhibitor. While VPA is known to cause teratogenic changes in the embryonic zebrafish brain, its effects on neural stem cells (NSCs) in both the embryonic and adult zebrafish are not well understood. Results: In this study, we observed a proliferative effect of VPA on NSCs in the embryonic hindbrain. In contrast, VPA reduced cell proliferation in the adult zebrafish optic tectum. Treatment with HDAC inhibitors showed a similar inhibitory effect on cell proliferation in the adult zebrafish optic tectum, suggesting that VPA reduces cell proliferation through HDAC inhibition. Cell cycle progression was also suppressed in the optic tectum of the adult zebrafish brain because of HDAC inhibition. Recent studies have demonstrated that HDAC inhibits the Notch signaling pathway; hence, adult zebrafish were treated with a Notch inhibitor. This increased the number of proliferating cells in the adult zebrafish optic tectum with down-regulated expression of her4, a target of Notch signaling. Conclusions: These results suggest that VPA inhibits HDAC activity and upregulates Notch signaling to reduce cell proliferation in the optic tectum of adult zebrafish.Developmental Dynamics 11/2014; 243(11). DOI:10.1002/dvdy.24173 · 2.38 Impact Factor
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