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Chromatin modification of Notch targets in olfactory receptor neuron diversification

Nature Neuroscience volume 15, pages 224–233 (2012)Cite this article

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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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Figure 1: Differential Notch signaling and Ham and Svp expression delineates ORN identity.
Figure 2: Naa, Nab and Nba identities in the ORN lineage.
Figure 3: ham mutant ORNs switch axonal projection identities.
Figure 4: Ham acts as a switch between Nab and Nba odorant receptor expression identity.
Figure 5: Modification of Notch activity by a Ham-CtBP complex.
Figure 6: Ham drives chromatin modification at Notch-target loci.
Figure 7: Ham controls ORN lineage Notch target dynamics.

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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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Author notes

  1. M Rezaul Karim and Hiroaki Taniguchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Keita Endo & Kei Ito

  2. Disease Mechanism Research Core, RIKEN Brain Science Institute, Wako, Saitama, Japan

    M Rezaul Karim, Hiroaki Taniguchi, Emi Kinameri, Matthias Siebert & Adrian W Moore

  3. Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK

    Alena Krejci & Sarah J Bray

  4. Faculty of Science, University of South Bohemia, Ceske Budejovice, Czech Republic

    Alena Krejci

  5. Institute of Entomology, Biology Centre of the Academy of Sciences of the Czech Republic, Ceske Budejovice, Czech Republic

    Alena Krejci

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Contributions

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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Correspondence to Adrian W Moore.

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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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