Dr. Campbell received his Ph.D. in 1987 with Peter Shelton at the University of Leicester, performed postdoctoral studies with Stanley Caveney at the University of Western Ontario and with Andrew Tomlinson at the MRC and Columbia University, and joined the Department in 1998.
The development of multicellular animals requires precise regulation of gene activity and cell behavior to control patterns of cell differentiation and final size and shape.
We use the fruit fly, Drosophila melanogaster, to answer questions such as: why is a gene switched off in one cell but not in another, and why are appendages generally long and thin rather than short and fat? Drosophila offers a wide range of genetic and molecular approaches and resources and, as genetic pathways are shared with other animals, the results from studies in flies help in understanding similar phenomena in other species, even to revealing mechanisms involved in human development and disease, such as cancer.
Not all of the genes in a cell are being activity transcribed; cells have to switch genes on and off to control their differentiation and to respond to various stimuli. Genes can be silenced by repressors - regulatory transcription factors - which bind to specific sequences adjacent coding regions and use various mechanisms to negatively influence transcription. Most repressors, such as the fly protein, Brinker, recruit secondary proteins, corepressors, including Groucho and CtBP. We are investigating why repressors such as Brinker need to recruit multiple corepressors and how these corepressors function to provide repressive activity.
Gradients and thresholds
In developing tissues, precise patterns of gene expression are established that presage the final pattern of differentiation. A common mechanism used to achieve this is the generation of a transcription factor gradient and the activation and repression of different target genes above distinct thresholds. For example, in the developing fly wing Brinker is expressed in symmetrical lateral-to-medial gradients (Fig. 1) and target genes sal and omb are expressed in overlapping, nested patterns with the omb domain wider than sal because omb is less sensitive to repression by Brk. We are studying how the Brk gradient is established and what determines how sensitive a gene is to repression by Brk.
Size and shape
Each organ or appendage, such as the fly wing, has to achieve the correct size and shape to function properly. The cellular mechanisms operating to generate the elongated morphology of the wing can be revealed by mutations which disrupt its shape and are beginning to show that regulating patterns of growth, cell movement and cell shape are key to morphogenesis of this appendage. We are characterizing several mutants, such as narrow (Fig. 2), to determine the relative importance of these processes at different stages of development.
Campbell, G., and S.J. Newfeld (2008) Current topics in organogenesis and gametogenesis. Fly 2:
Wehn, A, and G. Campbell (2006) Genetic interactions among scribbler, Atrophin and groucho in Drosophila uncover links in transcriptional repression. Genetics 173:849-861
Moser, M., and G. Campbell (2005) Generating and interpreting the Brinker gradient in the Drosophila wing. Dev. Biol. 286:647-658
Campbell, G. (2005) Regulation of gene expression in the distal region of the Drosophila leg by the Hox11 homolog, C15. Dev. Biol. 278:607-618
Winter, S.E., and G. Campbell (2004) Repression of Dpp targets in the Drosophila wing by Brinker. Development 131:6071-6081
Campbell, G. (2002) Distalization of the Drosophila leg by graded EGF-receptor activity. Nature 418:781-785
Wang, S., A. Simcox, and G. Campbell (2000) Dual role for Drosophila epidermal growth factor receptor signaling in early wing disc development. Genes Dev. 14:2271-2276
Campbell, G.L., and A. Tomlinson (2000) Transcriptional regulation of the Hedgehog effector CI by the zinc-finger gene combgap. Development 127:4095-4103