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

In Drosophila, defects in asymmetric cell division can result in the formation of stem cell derived tumors. Here, we reveal a different mechanism that can result in the formation of very similar terminal brain tumor phenotypes. We demonstrate that brain tumors in l(3)mbt mutants originate from overproliferation of neuroepithelial cells in the optic lobes caused by de-repression of target genes in the Salvador-Warts-Hippo (SWH) pathway. We use ChIP-seq to identify L(3)mbt-binding sites and show that L(3)mbt binds to chromatin insulator elements. Mutating l(3)mbt or inhibiting the insulator protein mod(mdg4) results in upregulation of SWH pathway reporters. As l(3)mbt tumors 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 tumor formation. Our data reveal that very different primary defects can result in the formation of brain tumors, which behave quite similarly in their advanced stages.