[Keywords: YAP; Lats; Mst; contact inhibition; NF2; Hippo] Supplemental material is available at http://www.genesdev.org.

The Drosophila gene eyeless (ey) encodes a transcription factor with both a paired domain and a homeodomain. It is homologous to the mouse Small eye (Pax-6) gene and to the Aniridia gene in humans. These genes share extensive sequence identity, the position of three intron splice sites is conserved, and these genes are expressed similarly in the developing nervous system and in the eye during morphogenesis. Loss-of-function mutations in both the insect and in the mammalian genes have been shown to lead to a reduction or absence of eye structures, which suggests that ey functions in eye morphogenesis. By targeted expression of the ey complementary DNA in various imaginal disc primordia of Drosophila, ectopic eye structures were induced on the wings, the legs, and on the antennae. The ectopic eyes appeared morphologically normal and consisted of groups of fully differentiated ommatidia with a complete set of photoreceptor cells. These results support the proposition that ey is the master control gene for eye morphogenesis. Because homologous genes are present in vertebrates, ascidians, insects, cephalopods, and nemerteans, ey may function as a master control gene throughout the metazoa.

SummaryThe Hippo pathway has emerged as a conserved signaling pathway that is essential for the proper regulation of organ growth in Drosophila and vertebrates. Although the mechanisms of signal transduction of the core kinases Hippo/Mst and Warts/Lats are relatively well understood, less is known about the upstream inputs of the pathway and about the downstream cellular and developmental outputs. Here, we review recently discovered mechanisms that contribute to the dynamic regulation of Hippo signaling during Drosophila and vertebrate development. We also discuss the expanding diversity of Hippo signaling functions during development, discoveries that shed light on a complex regulatory system and provide exciting new insights into the elusive mechanisms that regulate organ growth and regeneration. Key words: Cell signaling, Drosophila, Mouse development, Organ growth control, Tumor suppressor genes IntroductionAlthough growth is fundamental to animal development, surprisingly little is known about the mechanisms that control organ size (Neto-Silva et al., 2009;Stanger, 2008). How, for example, do cells know when to stop dividing after an organ has reached its correct size? How do injured organs regenerate damaged parts, and how do cells sense that part of an organ is missing? Over the past two decades, much progress has been made in deciphering the mechanisms that are responsible for tissue patterning, while the mechanisms that control organ size have remained largely a mystery.A puzzling but fascinating aspect of growth control in many animal species is that the number of divisions that a cell can undertake is often not programmed into organ progenitor cells, which may thus exhibit a variable number of cell divisions. This feature of growing tissues makes compensation for the loss of cells during development possible, a phenomenon referred to as regulative development. For example, mouse embryos that have been reduced to 10% of their normal size by administration of mitomycin C just before the onset of organogenesis engage a compensatory growth program, resulting in nearly normal sized embryos 48 hours later (Snow and Tam, 1979). Compensatory proliferation also occurs in Drosophila imaginal discs. For example, larvae in which over 60% of imaginal disc cells have been ablated by X-rays produce normal sized adults (Haynie and Bryant, 1977). Even more remarkably, some adult animals have the ability to regenerate missing parts: salamanders and crickets, for example, can regenerate entire limbs after amputation (Bryant et al., 1977; French et al., 1976). A major conclusion from such compensation and regeneration experiments is that cell-to-cell signaling is required to regulate cell proliferation as a function of organ size. The identity of these signals, however, remains largely unknown (Affolter and Basler, 2007;Neto-Silva et al., 2009;Stanger, 2008).The recent discovery of the Hippo pathway as a key regulator of organ growth in Drosophila has generated much excitement, as it provides novel insight into the mec...

The Hippo signaling pathway is an emerging growth control and tumor suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signaling and hyperactivation of its downstream effectors YAP and TAZ contribute to the development of cancer, suggesting that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also play beneficial roles in stimulating tissue repair and regeneration following injury, therefore activation of YAP and TAZ may be useful in these contexts. Recently, a complex network of intracellular and extracellular signaling pathways that modulate YAP and TAZ activities have been identified. Here we review the regulation of the Hippo signaling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small molecule pathway modulators.