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The tumour suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements

Nature Cell Biology volume 13, pages 1029–1039 (2011)Cite this article

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Abstract

In Drosophila, defects in asymmetric cell division often result in the formation of stem-cell-derived tumours. Here, we show that very similar terminal brain tumour phenotypes arise through a fundamentally different mechanism. We demonstrate that brain tumours in l(3)mbt mutants originate from overproliferation of neuroepithelial cells in the optic lobes caused by derepression of target genes in the Salvador–Warts–Hippo (SWH) pathway. We use ChIP-sequencing to identify L(3)mbt binding sites and show that L(3)mbt binds to chromatin insulator elements. Mutating l(3)mbt or inhibiting expression of the insulator protein gene mod(mdg4) results in upregulation of SWH pathway reporters. As l(3)mbt tumours are rescued by mutations in bantam or yorkie or by overexpression of Expanded, the deregulation of SWH pathway target genes is an essential step in brain tumour formation. Therefore, very different primary defects result in the formation of brain tumours, which behave quite similarly in their advanced stages.

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Figure 1: l(3)mbt is necessary to prevent tumorous overproliferation of the larval central nervous system.
Figure 2: Candidate screen reveals a function for the SWH pathway in optic lobe proliferation.
Figure 3: SWH target genes are misregulated in l(3)mbt mutants.
Figure 4: The SWH pathway shows genetic interaction with l(3)mbt.
Figure 5: L(3)mbt localizes to the nucleus.
Figure 6: L(3)mbt binds at the TSS and regulates SWH target genes and JAK–STAT pathway activity.
Figure 7: L(3)mbt binds at insulator-bound regulatory domains and influences Abd-B expression

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Acknowledgements

We wish to thank I. Reichardt, N. Corsini, A. Fischer and C. Jueschke for comments on the manuscript; R. Neumueller and all former and present members of the Knoblich laboratory, as well as W. Wei, C. Girardot and J. Gagneur for discussions; R. Lehmann, D. Pan, L. Zhang, N. Tapon, B. Thompson, G. Halder, G. H. Baeg, M. Labrador, the Flytrap Yale, the Bloomington Drosophila Stock Center, the Vienna Drosophila RNAi Center and the Developmental Studies Hybridoma Bank for fly stocks, antibodies and constructs; P. Serrano Drozdowskyj and M. Novatchkova for bio-informatic support; M. Madalinski for affinity purification; E. Kleiner for technical assistance; K. Aumayr, P. Pasierbek and G. Schmauss for bio-optics support; and S. F. Lopez, S. Wculek and C. Valenta for fly work support. Work in J.A.K.’s laboratory is supported by the Austrian Academy of Sciences, the Austrian Science Fund (FWF) and the EU FP7 network EuroSystem.

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  1. Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria

    Constance Richter, Jonas Steinmann & Juergen A. Knoblich

  2. European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany

    Katarzyna Oktaba & Jürg Müller

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  1. Constance Richter
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Contributions

C.R. conceived and conducted experiments, coordinated the project and wrote the manuscript. K.O. conducted the bio-informatics analysis and conducted experiments. J.S. wrote the peakfinder software and mapped the Solexa reads. J.M. supervised the project. J.A.K. initiated, designed and supervised the project, conceived experiments and wrote the paper.

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Correspondence to Juergen A. Knoblich.

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Richter, C., Oktaba, K., Steinmann, J. et al. The tumour suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements. Nat Cell Biol 13, 1029–1039 (2011). https://doi.org/10.1038/ncb2306

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