During animal development, tissues grow tremendously in size, growing roughly 1000-fold from the embryo to the adult. Each tissue then stops growing at a very precise size, which is determined by a combination of genetic and environmental factors. The precision of this growth controlling mechanism is illustrated by the fact that our limbs on the left and right sides of the body are basically identical in size. Surprisingly, the mechanisms controlling tissue growth are not yet understood. The lab is interested in studying signaling pathways that regulate tissue growth. These include:

(1) Insulin
(2) Warts/Hippo
(3) Dpp (TGF-beta in mammals)

These signaling pathways play important roles not only during normal animal development, but also in cancer, where uncontrolled tissue growth is one hallmark of the disase. Since tissue growth requires biosynthetic building blocks and substantial amounts of energy, these signaling pathways also impact cellular and organismal metabolism.

Since these signaling pathways are conserved from flies to humans, we use Drosophila as a model system for gene discovery and function elucidation. In fact, many components in these pathways were first discovered in the fly. The fly provides some major advantages, including a small genome, powerful genetic tools, and short reproductive cycle. This means, for instance, that knockout flies can be generated very quickly to assay gene function at the organismal level, at a speed that would not be possible with mammalian systems. We then translate our findings into mammalian systems.



Examples of individual projects are listed below:

TOR is a central regulator of cell growth. Highly conserved from yeast to humans, it is one of the most powerful anabolic signals in a cell. Basically, when TOR is active, cells accumulate mass and grow, whereas when TOR is inactive, cells cannot grow. For this reason, TOR is activated in almost all human cancers. TOR promotes cell growth by inducing protein synthesis, as well as synthesis of other cellular building blocks such as lipids for the cell membrane. Because of its central role in regulating growth, TOR activity is regulated by a large number of inputs including growth factor signaling (such as insulin), cellular stresses (such as hypoxia, or high AMP levels) as well as the availability of amino acids. The molecular mechanisms by which some of these inputs regulate TOR, however, are still not understood. This project aims to identify novel regulators of TOR, in particular relating to cellular amino acid sensing, and to understand their function both at the molecular level and at the physiological level. This project recently received funding from the prestigious ERC Starting Grants!

In collaboration with the Boutros Lab, this project will start by performing cell-based RNAi screens to identify regulators of TOR in Drosophila and human cells. We will then study genes identified in this screen both in cell culture to understand mechanism of action, as well as in live animals by generating knockout flies and studying their physiology. In this manner, we will bridge the divide from the gene to the animal.

Diabetes is a significant and growing medical problem and burden to our society. It is estimated that roughly 1 in 3 people born today in the western world will develop diabetes in their lifetime. Despite this, surprisingly, the molecular cause of diabetes is not yet known.

Two important players in diabetes are the insulin signaling pathway and mitochondria. The insulin signaling pathway controls whether a cell uses energy and nutrients, or not. Mitochondria are the major site of energy production in the cell, as well as the site of lipid oxidation. On the one hand, preliminary data suggest that impaired insulin signaling in diabetic patients affects the ability of mitochondria to function properly. On the other hand, impaired mitochondrial function appears to lead to an accumulation of lipids, which impairs insulin signaling. One project in the lab aims to unravel these interconnections, and to understand how insulin signaling regulates mitochondrial function and vice-versa. This project is part of a larger, international consortium funding by the EU FP7, called MITIN. Please look here for the project website.

Insulin signaling regulates several important aspects of animal physiology, including tissue growth, carbohydrate metabolism, lipid metabolism, and aging. When insulin signaling is aberrantly up-regulated, it leads to cancer. Aberrantly down-regulated insulin signaling (insulin resistance) leads to metabolic diseases such as diabetes and obesity. Despite having been studied for many years, the molecular mechanisms of insulin signaling are not fully understood. Components are still missing, and the molecular outputs of the pathway remain elusive. Several projects in the lab aim at studying new components of insulin signaling, as well as better understanding how outputs of the pathway regulate cell behavior.

During animal development, tissues grow tremendously in size. For instance, during Drosophila development, the wing is specified as a group of 50 cells which then proliferate to yield a tissue with 50,000 cells. When tissues reach their correct final size, the cells in the tissue stop proliferating. The molecular mechanism by which this occurs is still mysterious. How tissues measure their size and know when to stop growing is a fundamental problem in developmental biology that is still unsolved. (For review see here.) Furthermore, it is a process of interest for cancer biology since the molecular pathways that control this process are linked to the re-initiation of proliferation that occurs in cancer. Drosophila has become one of the principal model systems to study this problem. A number of projects in the lab aim at discovering novel genes regulating this process.