Carmen Coelho

PhD,Tata Institute of Fundamental Research,Mumbai

I am interested in elucidating the determinants of invertebrate and vertebrate organ and body size and currently use the fruit fly Drosophila melanogaster as a model for my studies. Like most people in the field I focus on growth of the wing imaginal discs, epithelial sac-like structures that grow and get patterned during larval life and then differentiate to form wings during pupation. What I have learnt from my recent work is that disc growth curves vary during normal development. I observed a high degree of variation in disc size during earlylarval life. This variation is compensated for during development and thus decreases towards the endof larval life.

Most, if not all current hypothetical models usedto explain how final disc size may be controlled areeither based on a rigid, inflexible growth curve orassume that size is sensed and monitored throughout development. These models assume that disc or organ growth rates correlate with disc size throughout development. My findings suggest that this is unlikely and that, instead, growth rates at any given time depend on "history" or the growth path the organ has undertaken until then.I have fitted mathematical models to my data and through simulations have shown that the variation in disc size during development can be brought down through growth-rate-dependent synthesis of hypothetical inhibitors. In such a model appropriate final size is achieved without sensing size during development. Certain assumptions about very early growth (the start of growth just after larval hatching) were incorporated in this model. I have begun validating these assumptions and testing a prediction that this model makes. This prediction is that if size is altered at the very start, before growth begins, the alteration will not be compensated and will result in abnormal final size. This also implies that egg size would become an important influence on final disc size. Thus we are examining the size of eggs under different culture conditions.

We have started a parallel line of work addressing the mechanism behind cell competition. Cell competition is a phenomenon first described in fly imaginal discs but later demonstrated across species,in particular in mouse early embryos. It is also implicated in cancer progression. It is a process by which faster growing cells eliminate their slower growing neighbours. This process has received much attention in the past decade and a number of genetic screens have been performed using the fly system to identify the molecules involved. Genes have been identified that are up regulated in the slower growing cells, or "losers", when faced with cell competition. It is postulated that the faster cells, or "winners", secrete factors that signal to the losers, killing them, but these factors have not been identified yet. We have set out to perform a genetic screen that we believe gives us an advantage over other screens that have been performed and could help identify these elusive factors.

These studies could provide a platform for studies that are relevant to human health and nutrition.Catch-up growth is an established phenomenon in mammals including humans and laboratory rodents. Variations in early growth rates due to a number of clinical and environmental causes do not always result in significant alterations of final body or organ size. Since growth is a fundamental process likely to be governed by conserved mechanisms, studies in the fruit fly should help guide studies in humans. On the same vein, our studies on cell competition could help us understand overgrowth disorders observed in humans due to somatic mutations that result in mosaicism. We are beginning to mimic these mutations in flies to examine their growth properties in a simple, tractable system.

The increase in size and shape complexity of the wing imaginal disc during its growth period spanning larval life. The picture on the left shows a fixed wing disc expressing GFP inside the larva, at approximately the start of larval life. The picture on the right shows a wing imaginal disc at the end of larval life dissected out of a larva and stained using Actin-binding (red) fluorophores. The blue colouration in both pictures is from a nuclear labelling fluorophore. Scale bar indicates 10 microns and 100 microns in pictures on the left and right respectively.

Selected publications:

1.Growth and cell survival are unevenly impaired in pixie mutant wing discs. Development, 132: 5411-5424 (2005). Coelho CMA, Kolevski B, Bunn C, Walker C, Dahanukar A, Leevers SJ

2. Do growth and cell division rates determine cell size in multicellular organisms? Journal of Cell Science, 113: 2927-2934 (2000). Coelho CM, Leevers SJ