Dr. Gerard Campbell

Genetics
K. Arndt
T.-L. Ashman
G. Campbell
D. Chapman
G. Hatfull
J. Hildebrand
L. Jacobson
S. Kalisz
J. Martens
W. Saunders
B. Stronach
S. Tonsor
R. Wood

Microbiology
J. Boyle
G. Hatfull
R. Hendrix
J. Lawrence
J. Pipas
M. Popa
R.L. Duda
S. Godfrey
V. Oke

Molecular Biology
K. Arndt
J. Franzen
P. Grabowski
G. Hatfull
R. Hendrix
L. Jen-Jacobson
J. Martens
C. Peebles
J. Pipas
J. Rosenberg
A. Schwacha
C. Walsh

Plant Biology
T.-L. Ashman
W. Carson
S. Kalisz
V. Oke
C. Partanen
S. Tonsor
B. Traw

Science Education
A. Bledsoe
K. Curto
L. Daniels
S. Godfrey
N. Kaufmann
C. LaFave
J. Newman
E. Polinko
M. Popa
L. Roberts
T. Seiflein
R. Sherwin
A. Slinskey Legg

Structural Biology
M. Grabe
J. Hempel
R. Hendrix
L. Jen-Jacobson
J. Rosenberg
A. VanDemark

Former Faculty

Photo of Dr.
Campbell

Molecular Genetics of Development in Drosophila

Associate Professor

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.

Currently, Dr. Campbell is accepting graduate students in his laboratory. Dr. Campbell is accepting undergraduate researchers, and does sponsor students in other laboratories.

Professional Interests - Publications - Contact Information - Lab Personnel

Professional Interests of Gerard Campbell

Multicellular animals are composed of hundreds of different cell types organized into precise spatial patterns to form functional units such as organs and appendages. Remarkably, all these cell types are derived from a single cell, the fertilized egg. How do cells become different during the course of embryogenesis (the final step in the process is differentiation) and how are these different cell types generated in the correct positions within developing tissues (the process of pattern formation or spatial patterning)? These are some of the basic questions of Developmental Biology and we are addressing them using the fruit fly, Drosophila, as a model organism. We use Drosophila because of the wealth of genetic data and the formidable array of genetic techniques developed for use in this organism. Most of the genetic and molecular mechanisms operating to direct development are shared by all animals from worms to insects to more complex animals such as ourselves, so that studies in Drosophila have helped us to understand how all animals develop. Understanding development can also provide insights into many human diseases, including birth defects which are the result of abnormal developmental processes, and different types of cancer which can be caused by misactivation of signaling pathways that normally operate to regulate development. Several of the genes involved in these human diseases were identified originally in Drosophila because mutations disrupt development in specific ways.

Fig. 1. Different views of the same wing imaginal. (a) The black holes mark cells that are mutant for the Mad gene (green cells are wild-type). (b) Expression of the brinker (brk) gene in red. (c) brk expression is normally excluded from the central region of the wing by Dpp signaling (see below, Fig 2), but is expressed there in cells mutant for Mad (arrowed). Mad is required in cells for Dpp signal transduction. It was the first member of the Smad family of proteins to be identified, these are required for transduction of all TGF-beta signals (Dpp is a TFG-beta). The human gene, Smad4 is frequently mutated or deleted in pacreatic and metastatic colon cancers.

Cell-cell signaling and the legs and wings of Drosophila
More specifically we study the factors that regulate the development of the legs and wings of flies. These appendages are derived from the imaginal discs of the larva (groups of 'embryonic' cells that develop into legs and wings inside the larva rather than in the embryo). Development of the legs and wings requires that cells communicate with each other so that they can determine their position within the imaginal disc and then differentiate appropriately. This communication is mediated largely by secreted polypeptide signaling molecules/growth factors. We are interested in how different secreted signaling molecules including Wnts, TGF-beta's and EGF-related molecules regulate the development of the leg and wing, asking questions such as: which factors are required, what is their role, do they function as morphogens, how are their signaling pathways regulated, what target genes (such as regulatory transcription factors) do they activate and what is the function of these targets? We employ a number of genetic and molecular techniques to answer these questions.

Fig. 2. One of the most powerful genetic techniques is simply to characterize the phenotype of loss of function mutants. This figure shows the effect of loss of EGF-receptor activity at different times on the development of the wing and the thorax using a temperature sensitive allele. (a) A wild-type fly. The notum (n) of a fly is the body wall of the thorax to which the wing (w) is attached. (b) Loss of EGF-receptor activity in the second instar larva results in the loss of the notum. (c) Loss of EGR-receptor activity in the first and early second instars results in the loss of both the wing and notum. This show that EGF-receptor activity is required at different times for the development of the wing and the notum.

Why is an insect not a worm? Formation of the proximodistal axis of the leg.
Insects (and all arthropods) are distinguished from other invertebrates such as worms by the possession of articulated appendages. Why do they have these outgrowths from the body wall? More technically the question can be addressed as: what controls the formation of the proximodistal axis, i.e. the sequence of cell types from the base (proximal) to the tip (distal; if you consider your own arm this sequence would be shoulder, humerus, ulna/radius and hand)? Previously, we showed that this is controlled in flies by a combination of two signaling molecules, Wg (a Wnt) and Dpp (a TGF-beta). Our more recent studies have implicated EGF-receptor signaling in this process and we are determining the exact role played by this signaling pathway in leg development. We are also investigating how different genes are activated at different positions along the P/D axis, in particular genes at the tip of the leg, including two transcription factors Aristaless (al) and Terminal (tal) and also examining the role these factors play in the differentiation of the tip.

Fig. 3. (a) A wild-type leg; this is divided up into segments along the proximodistal (P/D) axis: the coxa (c), femur (f), trochanter (tr), tarsus (tr) and at the tip there is a pair of claws. (b) Leg imaginal disc; the P/D axis corresponds to the radius of the disc so that the presumptive tip is in the center (during metamorphosis the leg 'telescopes' out). The formation of the P/D axis is regulated by Wg and Dpp which are expressed in a ventral sector and dorsal stripe, respectively. (c) Al is expressed at the presumptive tip, in the center of the disc (and also more proximally). (d) Tip of a wild-type leg showing the claws. (e) al mutant in which the claws are absent. (f) Egfr mutant in which the claws are also absent.

How do morphogens work? Regulation of Dpp signaling in the wing.
A morphogen is a substance that can elicit different developmental responses in a concentration dependent manner, i.e. high levels tell cells to do one thing whilst lower levels tell them to do something else. Several secreted signaling molecules have been shown to act as morphogens and one of the best examples is Dpp in the Drosophila wing, where it controls the formation of cell types along the anteroposterior (A/P) axis (in human terms this would be thumb, 1st finger, 2nd finger, 3rd finger then pinky). In simple terms, high levels tell cells they are in the center of the wing, low levels that they are at the edge. In molecular terms, genes required for development of the center of the wing are activated by high levels of Dpp signaling, while genes required for the development of the edge of the wing are activated by low levels. How can the same signaling pathway activate expression of different genes in cells simply based on the level of signaling activity? Dpp signaling actually controls gene expression, in part, indirectly by turning off expression of a transcription factor, Brinker (Brk), that represses expression of these genes. We are investigating how Dpp regulates Brk expression and how Brk represses expression of genes required for wing development.

Fig. 4. Regulation of patterning along the A/P axis of the wing by Dpp and Brk. (a) Wing imaginal disc showing dpp expression in the center of the A/P axis. (b) Adult wing indicating where dpp was expressed. (c) Dpp protein is secreted and forms a gradient in the anterior and posterior halves of the wing. (d) brk is expressed at the anterior and posterior extremes of the wing, being repressed in the center by Dpp signaling (see also, Fig 1). (e) Loss of brk in a small group of cells in the posterior region of the wing (where brk is normally expressed) results in an aberrant outgrowth (arrow) indicating brk is required in this region to regulate growth and development of the wing. (f) Ubiquitous expression of brk results in almost complete loss of the wing indicating it must be downregulated in the central regions of the A/P axis by Dpp to allow development of the wing.

Publication Archive
15 Citations
15 Abstracts
15 PDFs

Recent Publications of Gerard Campbell

Wehn, A, and G. Campbell (2006) Genetic interactions among scribbler, Atrophin and groucho in Drosophila uncover links in transcriptional repression. Genetics 173:849-861 (PDF Reprint: 1.4 MB)

Moser, M., and G. Campbell (2005) Generating and interpreting the Brinker gradient in the Drosophila wing. Dev. Biol. 286:647-658 (PDF Reprint: 908 kb)

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 (PDF Reprint: 917 kb)

Winter, S.E., and G. Campbell (2004) Repression of Dpp targets in the Drosophila wing by Brinker. Development 131:6071-6081 (PDF Reprint: 1.5 MB)

Campbell, G. (2002) Distalization of the Drosophila leg by graded EGF-receptor activity. Nature 418:781-785 (PDF Reprint: 475 kb)

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 (PDF Reprint: 4.8 MB)

Campbell, G.L., and A. Tomlinson (2000) Transcriptional regulation of the Hedgehog effector CI by the zinc-finger gene combgap. Development 127:4095-4103 (PDF Reprint: 488 kb)

How to Contact Gerard Campbell

US Mail
University of Pittsburgh
Department of Biological Sciences
203A Life Sciences Annex
4249 Fifth Avenue
Pittsburgh, PA 15260

Phone, FAX, Internet
Office : (412) 624-6812
Lab : (412) 624-5865
FAX : (412) 624-4759
Email : camp+@pitt.edu
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