Abstract
Neuronal-class diversification is central during neurogenesis. This requirement is exemplified in the olfactory system, which utilizes a large array of olfactory receptor neuron (ORN) classes. We discovered an epigenetic mechanism in which neuron diversity is maximized via locus-specific chromatin modifications that generate context-dependent responses from a single, generally used intracellular signal. Each ORN in Drosophila acquires one of three basic identities defined by the compound outcome of three iterated Notch signaling events during neurogenesis. Hamlet, the Drosophila Evi1 and Prdm16 proto-oncogene homolog, modifies cellular responses to these iteratively used Notch signals in a context-dependent manner, and controls odorant receptor gene choice and ORN axon targeting specificity. In nascent ORNs, Hamlet erases the Notch state inherited from the parental cell, enabling a modified response in a subsequent round of Notch signaling. Hamlet directs locus-specific modifications of histone methylation and histone density and controls accessibility of the DNA-binding protein Suppressor of Hairless at the Notch target promoter.
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Acknowledgements
We thank L. Luo, T. Hummel, Y. Hiromi, Y.N. Jan, F. Matsuzaki, S. Parkhurst, the Bloomington Drosophila Stock Center, Bloomington Drosophila Genomics Resource Center, the Iowa Developmental Studies Hybridoma Bank and Flybase for Drosophila stocks, DNA clones, antibodies and indispensable database information, and C. Yokoyama and members of the Moore laboratory for advice on the manuscript. Funding was provided by Japan Society for the Promotion of Science Grants-in-Aid Young Scientists (B) to H.T. and Scientific Research (C) to K.E., a RIKEN–Deutscher Akademischer Austauschdienst Research Internship Scholarship to M.S., a Medical Research Council program grant to S.J.B., and a RIKEN Brain Science Institute core award to A.W.M.
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K.E., M.R.K., E.K., M.S., S.J.B. and A.W.M. carried out genetic analyses. H.T., A.K., E.K. and M.S. carried out molecular biology. K.E., K.I., S.J.B. and A.W.M. wrote the paper. A.W.M. conceived and coordinated the study.
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Endo, K., Karim, M., Taniguchi, H. et al. Chromatin modification of Notch targets in olfactory receptor neuron diversification. Nat Neurosci 15, 224–233 (2012). https://doi.org/10.1038/nn.2998
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DOI: https://doi.org/10.1038/nn.2998
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