Editors' ChoiceCell Biology

Ajuba links mechanical tension to cell cycle reentry

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Sci. Signal.  25 Aug 2015:
Vol. 8, Issue 391, pp. ec238
DOI: 10.1126/scisignal.aad2817

In many tissues, local stem cells maintain tissue homeostasis and mediate regeneration after injury. However, tissue damage can induce normally quiescent, differentiated cells to reenter the cell cycle to mediate repair. In Drosophila melanogaster imaginal discs, expression of a transgene encoding the apoptosis-promoting protein Hid induces widespread cell death followed by extrusion of dying cells from the epithelium and compensatory proliferation of the remaining epithelial cells. Hippo signaling inhibits cell proliferation by causing the phosphorylation and cytoplasmic retention of the transcriptional coactivator factor Yorkie (Yki, known as Yap in vertebrates). Yki cooperates with the transcription factor Scalloped (Sd) to promote the expression of genes required for cell proliferation. Meserve et al. found that tissue damage induced by Hid overexpression caused quiescent cells of the Drosophila eye imaginal disc to reenter the cell cycle through a Hippo pathway–dependent mechanism. Yki and its partner Sd were required for compensatory proliferation of epithelial cells in damaged Drosophila eye discs and stimulated the production of cyclin E, a known target of Yki and Sd that promotes cell proliferation. Compensatory proliferation also required the LIM domain protein Ajuba. Ajuba localizes to cell junctions and antagonizes Hippo signaling by preventing kinases downstream of Hippo from phosphorylating Yki. In the Drosophila wing disc, wounding triggers c-Jun N-terminal kinase (JNK) signaling, which in turn activates Ajuba to stimulate compensatory proliferation of epithelial cells in a Yki-dependent manner. In the eye disc, however, JNK signaling was not required for compensatory proliferation. Instead, results were consistent with wounding-induced increases in mechanical tension activating Ajuba. The authors speculate that forces exerted by the extrusion of dying cells from the epithelium directly activate Ajuba to down-regulate Hippo signaling and enable Yki and Sd to stimulate the expression of genes that drive cell cycle reentry.

J. H. Meserve, R. J. Duronio, Scalloped and Yorkie are required for cell cycle re-entry of quiescent cells after tissue damage. Development 142, 2740–2751 (2015). [PubMed]