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Abstract
The Spectrin cytoskeleton is known to be polarised in epithelial cells, yet its role remains poorly understood. Here, we show that the Spectrin cytoskeleton controls Hippo signalling. In the developing Drosophila wing and eye, loss of apical Spectrins (alpha/beta-heavy dimers) produces tissue overgrowth and mis-regulation of Hippo target genes, similar to loss of Crumbs (Crb) or the FERM-domain protein Expanded (Ex). Apical beta-heavy Spectrin binds to Ex and co-localises with it at the apical membrane to antagonise Yki activity. Interestingly, in both the ovarian follicular epithelium and intestinal epithelium of Drosophila, apical Spectrins and Crb are dispensable for repression of Yki, while basolateral Spectrins (alpha/beta dimers) are essential. Finally, the Spectrin cytoskeleton is required to regulate the localisation of the Hippo pathway effector YAP in response to cell density human epithelial cells. Our findings identify both apical and basolateral Spectrins as regulators of Hippo signalling and suggest Spectrins as potential mechanosensors.
Highlights
The Hippo pathway transduces signals from the cell surface to the nucleus to control tissue growth and regeneration in animals (Pan, 2010; Halder & Johnson, 2011; Tapon & Harvey, 2012)
We identified the apical Spectrin cytoskeleton components a-Spectrin (a-Spec) and b-heavy Spectrin— known as Karst (Kst)—as producing moderate wing and eye overgrowth phenotypes, similar to RNAi knock-down of Crb (Fig 1A–F and Supplementary Figs S1 and S2)
The Spectrin cytoskeleton is polarised in Drosophila epithelia, with dimers of a- and bH-Spec/Kst localising to the apical domain and dimers of a- and b-Spec localising to the basolateral domain (Thomas & Kiehart, 1994; Lee et al, 1997; Thomas et al, 1998; Thomas & Williams, 1999; Zarnescu & Thomas, 1999; Medina et al, 2002)
Summary
The Hippo pathway transduces signals from the cell surface to the nucleus to control tissue growth and regeneration in animals (Pan, 2010; Halder & Johnson, 2011; Tapon & Harvey, 2012). Several proteins can act upstream of the core kinase cascade, including the apical FERM-domain proteins Expanded (Ex; similar to both FRMD6 and AMOT proteins in humans) and Merlin (Mer; the NF2 tumour suppressor in humans), which act in parallel with activate Hippo signalling (Hamaratoglu et al, 2006; Irvine, 2012). Mutants in crb cause a mild overgrowth phenotype in wing and eye epithelia (Chen et al, 2010; Ling et al, 2010). Ex, kib or kib, mer double mutants cause a strong hpo-like overgrowth phenotype, suggesting that the three proteins act together upstream of the core kinase cascade (Baumgartner et al, 2010; Genevet et al, 2010; Yu et al, 2010). Ex, kib double mutants strongly affect polarisation of Crb in the ovarian follicular epithelium and polarisation of the actin cytoskeleton for border cell migration, functions that are independent of nuclear signalling via Yki (Fletcher et al, 2012; Lucas et al, 2013)
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