Hippo signaling in Drosophila: recent advances and insights

Abstract

The Hippo signaling pathway emerged from studies of Drosophila tumor suppressor genes, and is now appreciated as a major growth control pathway in vertebrates as well as arthropods. As a recently discovered pathway, key components of the pathway are continually being identified, and new insights into how the pathway is regulated and deployed are arising at a rapid pace. Over the past year and a half, significant advances have been made in our understanding of upstream regulatory inputs into Hippo signaling, key negative regulators of Hippo pathway activity have been identified, and important roles for the pathway in regeneration have been described. This review describes these and other advances, focusing on recent progress in our understanding of Hippo signaling that has come from continued studies in Drosophila.

Figure 1. Schematic model of the Hippo signaling network

The model depicts most identified components of the Drosophila Hpo pathway, grouped into modules as discussed in the text. These include the Hpo kinase cassette (outlined in green), the Mer-ex complex (outlined in purple), the Fat branch of the pathway (outlined in orange), and transcription factors (within nucleus, shaded grey). Arrows depict key regulatory connections, pointed arrows show activating effects, block arrows show inhibiting effects.

Figure 2. Examples of Hpo pathway phenotypes

A) Adult fly with a wts mutant clone in the notum, resulting in a tumorous overgrowth (image courtesy of Tian Xu, see (Xu et al., 1995) for details). B) Portion of a wing imaginal disc with wts mutant clones, identified by lack of green staining; two examples are outlined by dashed lines. In wild-type cells, Yki (red) is predominantly cytoplasmic), but in wts mutant cells it is readily detected in the nucleus, resulting in uniform distribution of Yki (reproduced from Oh and Irvine, 2008). Panel B’ shows only the Yki stain. C) Close-up of the intestine of an adult fly. D) Close-up of the intestine of an adult fly in which an activated form of Yki (Yki^S168A) is expressed within the differentiated cells. This stimulates an overproliferation of ISCs, and results in a massive overgrowth of the intestine (reproduced from Staley and Irvine, 2010).