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

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. Drosophila L(3)mbt mutant brains are shown to develop brain tumours owing to derepression of the target genes of the Salvador–Warts–Hippo pathway, resulting in overproliferation of neuroepithelial cells in the optic lobes. L(3)mbt is found to act in this process by binding to insulator elements at the promoters of these target genes.

Cite this article

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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