The unfolding of the Hippo signaling pathway.

The development of a functional organ requires not only patterning mechanisms that confer proper identities to individual cells, but also growth-regulatory mechanisms that specify the final size of the organ. At the turn of the 21st century, comprehensive genetic screens in model organisms had successfully uncovered the major signaling pathways that mediate pattern formation in metazoans. In contrast, signaling pathways dedicated to growth control were less explored. The past two decades has witnessed the emergence of the Hippo signaling pathway as a central mediator of organ size control through coordinated regulation of cell proliferation and apoptosis. Here I reflect on the early discoveries in Drosophila that elucidated the core kinase cascade and transcriptional machinery of the Hippo pathway, highlight its deep evolutionary conservation from humans to unicellular relatives of metazoan, and discuss the complex regulation of Hippo signaling by upstream inputs. This historical perspective underscores the importance of model organisms in uncovering fundamental and universal mechanisms of life processes.