Research

The lab is interested in 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 both in normal animal development and in disease - in particular cancer. Because 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 completely 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:

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.

The insulin signaling pathway has a large number of transcriptional outputs which regulate cellular growth and metabolism. These outputs are controlled by a network of transcription factors. Using transcriptional profiling and ChIP/chip techniques, we've started dissecting this network. We are now elucidating the cascade of transcription factors which activate each other, and the feedback loops in the network. Furthermore, the insulin signaling pathway regulates transcription in a tissue specific manner. For instance, there are genes which are up-regulated in response to insulin signaling in adipose tissue, but are down-regulated in muscle. We now have a database of tissue-specific outputs of the pathway, and can start mining this database to understand how the transcriptional network downstream of insulin signaling interacts with tissue-specific factors to yield tissue-specific outputs. The final goal is to elucidate the regulatory network by which insulin signaling impacts cellular transcription.

One particular focus is to understand how insulin signaling regulates mitochondrial function, in part via transcriptional mechanisms, as part of an EU FP7 funded project called MITIN. Please look here for the project website.

Using an overexpression screen, we searched for genes involved in tissue growth and metabolism. One gene we identified was a micro-RNA, miR-278. As an illustration of its growth-promoting activity, over-expression of miR-278 specifically in the eye causes eye hyperplasia.
This example illustrates the beauty of the genetic tools available in the fly, which allow easy overexpression of genes in a temporally-controlled, tissue-specific manner. By homologous recombination we generated a miR-278 knockout fly and showed that it has reduced adiposity and is insulin resistant in its adipose tissue. We then used a combination of computational biology and wet-lab experiments to show that the microRNA is working through a target, called Expanded, a growth-suppressor and component of the Hippo pathway.

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.