Nicolas Tapon

Control of tissue size during development and disease

In developing from a single-celled embryo to an adult, higher organisms accumulate mass at a rapid rate. Once each organ has reached the requisite size, cell proliferation and growth ceases in most of the tissue and will remain confined to specialised cells (such as stem cells) to maintain homeostasis throughout adult life. In order to achieve consistent organ and body size in individuals of the same species, tight control must be applied to cell growth and cell number at the end of development. Since the processes that restrict organ size are likely to be targets of tumour-promoting mutation, the study of these mechanisms is relevant to both developmental and cancer biology.

Hippo (Hpo), the Drosophila ortholog of MST1/2 (Mammalian Sterile 20-like) is a key regulator of an emerging signalling pathway that controls both cell death and proliferation ¹. This pathway is so far composed of two cytoskeletal proteins, Expanded (Ex) and Merlin (Mer), two serine/threonine kinases Hpo and Warts (Wts), the scaffold proteins Salvador (Sav) and Mats, as well as the transcriptional coactivator Yorkie (Yki). Loss of signalling via the Hpo pathway results in overgrown tissues containing excess cells.

The immediate aim of the lab is to identify new members of the Hpo pathway and to understand how the pathway functions at the biochemical level. In particular, we have little understanding of key issues, such as how Hpo becomes activated at the appropriate time during development, and how the cell discriminates between an apoptotic response or a cell cycle arrest response (presumably based on signal strength and/or cellular signalling context).

Upstream regulation of Hpo would likely need to integrate morphogenetic cues such as Dpp/TGFb and Wg/Wnt signalling, as well as other growth regulatory pathways (e.g. JAK/STAT, Egfr, Delta/Notch, InR) that participate in overall size control. Ultimately, we therefore want to understand how the Hpo pathway fits in the "big picture" of overall size regulation in development.

In order to achieve these aims, we use a combination of genetics, imaging, biochemistry and cell culture-based high-throughput RNA interference (RNAi) ^{2, 3}. Typical projects would include performing a genetic or RNAi screen and using the amazing array of Drosophila genetic tools to study gene function in vivo.

References

1. Harvey K and Tapon N. The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nat Rev Cancer 2007; 7: 182-191.
2. Polesello C, Huelsmann S, Brown NH and Tapon N. The Drosophila RASSF homolog antagonizes the hippo pathway. Curr Biol2006; 16: 2459-2465.
3. Colombani J, Polesello C, Josue F and Tapon N. Dmp53 activates the Hippo pathway to promote cell death in response to DNA damage. Curr Biol 2006; 16: 1453-1458.