The Salvador/Warts/Hippo pathway controls regenerative tissue growth in Drosophila melanogaster

Abstract

During tissue regeneration, cell proliferation replaces missing structures to restore organ function. Regenerative potential differs greatly between organs and organisms; for example some amphibians can regrow entire limbs whereas mammals cannot. The process of regeneration relies on several signaling pathways that control developmental tissue growth, and implies the existence of organ size-control checkpoints that regulate both developmental, and regenerative, growth. Here we explore the role of one such checkpoint, the Salvador-Warts-Hippo pathway, in tissue regeneration. The Salvador-Warts-Hippo pathway limits tissue growth by repressing the Yorkie transcriptional co-activator. Several proteins serve as upstream modulators of this pathway including the atypical cadherins, Dachsous and Fat, whilst the atypical myosin, Dachs, functions downstream of Fat to activate Yorkie. Using Drosophila melanogaster imaginal discs we show that Salvador-Warts-Hippo pathway activity is repressed in regenerating tissue and that Yorkie is rate-limiting for regeneration of the developing wing. We show that regeneration is compromised in dachs mutant wing discs, but that proteins in addition to Fat and Dachs are likely to modulate Yorkie activity in regenerating cells. In conclusion our data reveal the importance of Yorkie hyperactivation for tissue regeneration and suggest that multiple upstream inputs, including Fat-Dachsous signaling, sense tissue damage and regulate Yorkie activity during regeneration of epithelial tissues.

Tumor suppression by cell competition through regulation of the Hippo pathway

“…We noted that a minority of scrib − clones in the hinge region of wing discs and in the posterior region of eye discs displayed some increase in ex-lacZ expression, which has been observed by other groups (13,20). Thirty-one percent of clones in the hinge and 16% of clones in the posterior eye had at least one cell in which ex-lacZ was up-regulated (Fig.…”

“…(Fig. 3G) (20). This non-cell-autonomous effect on Hippo signaling also was observed around scrib − clones rescued from elimination: scrib − clones in M +/− tissues showed non-cell-autonomous effects on ex-lacZ (Fig.…”

“…S7 A-D). Non-cell-autonomous regulation of Hippo signaling by abnormal or damaged cells has been observed previously and has been suggested as a mechanism for ensuring that compensatory growth restores the tissue (19,20).…”

“…It has been reported that cells with compromised Scrib or Lgl function exhibit elevated activity of Yorkie (Yki), a transcriptional coactivator and downstream effector of the Hippo growthcontrol pathway (13,14,(18)(19)(20). The Hippo pathway is a conserved tumor-suppressor pathway that suppresses growth by antagonizing the activity of Yki (21).…”

Molecular mechanism of size control in development and human diseases

“…Fat and Dachsous, etc), and cell polarity (e.g. scribble, stardust, fat, LKB, etc) also have dramatic effect on final organ size (for review see references [162,163] and [106]). These genes may function as 'organ-size checkpoints' that regulate cell proliferation, cell death, and cell growth.…”