GSE96887
Organ growth control in the absence of Hippo signaling
Organs of all animals reliably grow to a specific size and it is widely thought that such developmental growth control is instructed by the Hippo signaling pathway. This is based on studies in flies and mice showing that deregulation of Hippo signaling causes dramatic tissue overgrowth of various organs. Here we use two major developmental paradigms and provide evidence that removing the key transcriptional downstream effectors of the Hippo pathway does not abolish organ growth control. Specifically, eliminating the function of the Hippo downstream co-activators Yki as well as Yap/Taz that complex with TEAD family transcription factors did not interfere with organ growth control in the developing mouse liver or Drosophila eye. Rather, mutant cells were able to proliferate appropriately during development, properly exit the cell cycle, and form organs of normal size. Remarkably, a complementing whole transcriptome analysis of mutant Drosophila eye imaginal discs corroborated these genetic findings. It showed that loss of the single TEAD transcription factor Scalloped (Sd) fully reverted the effect of overexpression of hyperactivated Yki back to a wildtype gene expression profile. In contrast, Sd/Yap/Taz proved to be crucial for cell survival in injury response models, namely X-ray irradiation of flies and toxic liver injury in mice. Therefore, we propose that Hippo signaling is dispensable for instructing normal organ growth and instead suggest that the classical Hippo mutant overgrowth phenotypes represent a de facto Yap/Taz/Yki gain-of-function situation that does not reflect an endogenous role in growth control. Instead, we hypothesize that the potency of Yap/Taz/Yki to drive tissue overgrowth draws from their broad and primary function in injury responses. Overall design: RNA-seq gene expression profiling across Drosophila 3rd instar larval wild type eye discs and genetic perturbations of Yki and sd.