The control of organ size is a long-standing puzzle in developmental biology. My laboratory uses Drosophila and mice as model systems to investigate size-control mechanisms in normal development and their pathological roles in cancer.
Our general approach is to use Drosophila as a genetic tool to discover size-control genes. We then use a combination of genetics and biochemistry to place these genes into signaling networks. Finally, we use mouse genetics to investigate how the size-control mechanisms we have uncovered in Drosophila regulate tissue homeostasis in mammals. With these concerted efforts, we aim to decipher the general mechanisms underlying control of organ size in animals.
To discover size-control genes, we conducted genetic screens in Drosophila for mutations that result in overgrowth of adult structures. These overgrowth mutants can be broadly divided into two classes: those associated with an increase in cell size and those associated with an increase in cell number.
Earlier studies from my laboratory focused on the cell-size mutants, which led to the discovery of a cell size-controlling pathway that involves the tuberous sclerosis tumor suppressors Tsc1 and Tsc2, the small GTPase Rheb, and the protein kinase TOR. The functional link between Tsc1 and Tsc2 and TOR uncovered in Drosophila paved the way for the clinical development of mTOR inhibitor everolimus in the treatment of subependymal giant cell astrocytoma associated with tuberous sclerosis.
Much of our recent work focused on the overgrowth mutants associated with an increase in cell number. These studies led us to elucidate the Hippo signaling pathway, which plays a critical role in stopping organ growth by simultaneously promoting cell death and cell cycle exit as cells enter the differentiation phase of organogenesis.
In Drosophila, the Ste20-like kinase Hippo (Hpo) phosphorylates and activates the NDR family kinase Warts (Wts). Wts, in turn, phosphorylates and inactivates the oncoprotein Yorkie (Yki) by excluding it from the nucleus, where it normally functions as a coactivator for the DNA-binding transcription factor Scalloped (Sd).
Building on insights from Drosophila, we further delineated a mammalian Hippo pathway that links the mammalian homologues of Hpo (Mst1/2), Wts (Lats1/2), Yki (YAP), and Sd (TEAD/TEF family members) in an analogous signaling cascade. Using a conditional YAP transgenic mouse model, we showed that the mammalian Hippo pathway is a potent regulator of organ size and that its dysregulation leads to tumorigenesis in mammals.
Our current and future research directions include:
- Elucidating the composition, mechanism and regulation of Hippo signaling using Drosophila as a model.
- Understanding the role of Hippo signaling in mammalian development, regeneration and tumorigenesis using mouse genetics.
- Investigating the ancestral role of Hippo signaling in unicellular organisms.
- Developing small-molecule modulators of the Hippo pathway for cancer and regenerative medicine.