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Review
. 2011 Jan;138(1):9-22.
doi: 10.1242/dev.045500.

Hippo signaling: growth control and beyond

Georg Halder  1 , Randy L Johnson
Affiliations
Review

Hippo signaling: growth control and beyond

Georg Halder et al. Development. 2011 Jan.

Abstract

The 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.

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Figures

Fig. 1.
Fig. 1.
Hippo mutant phenotypes in flies and mice. (A,B) Scanning electron micrographs of (A) a wild-type fly and (B) a fly with clones of cells homozygous mutant for hippo that exhibit overgrowth of the adult cuticle (Udan et al., 2003). (C) A mouse liver at 2 months of age from a wild-type animal and (D) a liver at 2 months of age from a mouse mutant in which both Mst1 and Mst2 (Stk3 and Stk4), two mammalian Hippo homologs, have been conditionally inactivated in the developing liver (Lee et al., 2010; Lu et al., 2010; Song et al., 2010; Zhou et al., 2009). The double null Mst1/2 mutant liver is overgrown owing to an increase in cell numbers.
Fig. 2.
Fig. 2.
Schematics of the Hippo pathway in flies and mice. Cells (outlined in grey, nuclei in green) are shown with adherens junctions (AJ) and basolateral junctions (BLJ). (A,B) Hippo pathway components in (A) Drosophila and (B) vertebrate are shown in various colors, with pointed and blunt arrowheads indicating activating and inhibitory interactions, respectively. Continuous lines indicate direct interactions, whereas dashed lines indicate unknown mechanisms. See text for further details. Abbreviations: Ajub, Ajuba; App, Approximated; Crb, Crumbs; Dco, Discs overgrown; Dlg, Discs large; Ds, Dachsous; Ex, Expanded; Fj, Four-jointed; Hth, Homothorax; Jub, Drosophila Ajuba; Lats, Large tumor suppressor; Lft, Lowfat; Lgl, Lethal giant larvae; Mer, Merlin; Mats, Mob as a tumor suppressor; Mob1A/B, Mps1 binder; Mst, Mammalian sterile 20 like; Rassf, Ras-associated factor; Sav, Salvador; Scrib, Scribble; Sd, Scalloped; Taz, transcriptional co-activator with PDZ-binding motif; TEAD, TEA domain protein; Tsh, Teashirt; Yap, Yes associated protein; Yki, Yorkie.
Fig. 3.
Fig. 3.
The polar coordinate model and Hippo signaling during organ growth. (A,B) Schematics representing the polar coordinate model to explain growth during (A) normal development and (B) regeneration. The schematics depict cells in growing tissues; the graded colors and the gradient lines indicate gradients of positional information or Dachsous (Ds) activity. When the difference of positional information between two neighboring cells exceeds a certain threshold, this triggers cell proliferation at the position of discontinuity (gray arrows) followed by intercalation of intermediate values. This `boundary effect' will drive proliferation until the gradient of positional information or Ds activity is smooth and differences between neighboring cells are below the threshold. (A) During development, gradients of positional information are steep initially, triggering intercalary proliferation until the tissue has reached its proper size and gradient of positional information. (B) During regeneration, after some cells are ablated (red crosses), cells at the wound site are juxtaposed to cells with inappropriate positional values (gray arrow), which triggers intercalary proliferation until the normal situation is restored. Ds activity is graded in developing Drosophila imaginal discs, reflecting positional information, and differences in Ds activity between neighboring cells can suppress the Hippo pathway and trigger proliferation (Rogulja et al., 2008; Willecke et al., 2008).
Fig. 4.
Fig. 4.
Recruitment of cells into the developing Drosophila wing by a Ds/Fj-dependent feed-forward signal. Schematics showing Dachsous (Ds) and Four-jointed (Fj) expression levels in the wing pouch area of a Drosophila wing imaginal disc. (A) Cells of the wing pouch (red) are specified by the expression of the wing selector gene vestigial (vg), which induces high levels of Fj expression, while cells surrounding the wing pouch (blue) express high levels of Ds. The gradients of Ds and Fj are thus steepest at the periphery of the vg-expressing wing pouch, which leads to suppression of Hippo signaling through the Ds boundary effect (gray arrows). (B) Suppression of Hippo signaling then leads to the induction of Hippo target genes, one of which is vg. Ds/Fj signaling thus results in the expansion of the vg expression domain (purple) and the Ds boundary effect acts as a recruitment signal (purple arrow) (Zecca and Struhl, 2010). (C) Vg in these newly recruited pouch cells induces Fj expression and causes suppression of Ds expression, which moves the Ds and Fj expression gradients outwards and leads to another cycle of signaling and recruitment of more neighboring cells, thereby further expanding the territory of the wing pouch (Zecca and Struhl, 2010). This growth control model is specific for the Drosophila wing and it can partially explain the control of growth of the developing wing. Other unknown mechanisms must act in addition, as ds,fj double mutant flies can still produce small wings (Rogulja et al., 2008; Willecke et al., 2008).
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