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- Worms in space
- Insights into birth defects from mice
- Signaling wars in worms
- Double danger for tadpoles
- The Secrets of Limb Developments in Flies
- New view of Phage Phylogeny
- Mouse genetics uncovers multiple roles for CtBP
- A New Look at Specificity
- Modified Proteins Found in Tumors
Pittsburgh Bacteriophage Institute
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We understand more about the molecular and genetic mechanisms regulating the development of the fruit fly, Drosophila, than any other multicellular organism.
Studies on flies have also helped us to understand how animals from other phyla develop, because many of the mechanisms are remarkably conserved.
For example, the HOX group of transcription factors regulate differentiation of cells along the anteroposterior axis (head to tail) of all bilaterally symmetric animals from worms to ourselves.
These similarities suggest that there was a common ancestor to all bilaterally symmetric animals, and that some of the developmental mechanisms it employed have been used, albeit in modified ways, by its descendents.
The Campbell lab is investigating limb development in Drosophila using the powerful array of genetic techniques developed in this species.
The limbs of flies are morphologically very distinct from those in vertebrates but recent studies in the Campbell lab have revealed that the same
signaling pathway may be regulating outgrowth and differentiation of cells along the proximodistal axis (base to tip) in limbs from both groups. Work in other labs has characterized the role of members
of the FGF family of secreted signaling molecules in limb outgrowth in vertebrates, where they are expressed at the tip of the developing appendage. Previous studies in flies suggested this process
was regulated very differently via members of the Wnt and TGF-b families of secreted factors which are expressed in ventral and dorsal stripes,
respectively, intersecting at the presumptive tip. However, the Campbell lab has revised our understanding of leg development in flies, showing differentiation along the proximodistal
axis of the tarsus of the leg, the evolutionarily 'ancient' portion, is actually regulated by signaling by EGF-related ligands, expressed at the tip of the developing leg, in a similar fashion to FGFs in vertebrate limbs.
EGFs and FGFs both activate the same family of membrane receptors, RTKs, stimulating the same intracellular signal cascades, implicating this pathway in limb outgrowth in both flies and vertebrates.
Figure 1. Regulation of leg development in flies by EGF-receptor (EGFR) signaling. (a) The tarsus of the Drosophila leg from a wild-type (wt) leg
is divided into five segments (I -V) and terminates in a pair of claws (cl). The tarsus is the evolutionarily 'ancient' portion of the insect leg. (b) Reduction in EGF-receptor signaling using a
temperature sensitive allele results in truncation of the tarsus. This is temperature dependent so that at high temperatures (when EGFR signaling is almost completely eliminated) the
tarsus is reduced to a single segment I, but at progressively lower temperatures (right to left, with progressively increased levels of EGFR activity) more tarsal segments develop.
This indicates that the distal-most tissue, the claws, requires the highest levels of EGFR activity while progressively more proximal tissue requires progressively less EGFR activity for development. This suggests that a distal-to-proximal gradient of EGFR is regulating development of the tarsus. This gradient is established from a source of EGF-related ligands at the presumptive tip of the developing leg (not shown).
These studies reveal a possible evolutionary link between appendage development in flies and vertebrates, suggesting the last common ancestor of most multicellular animals may have
possessed an appendage or body wall outgrowth of some form and that RTK signaling was used to regulate its development. Previous studies from other labs on the Distal-less (Dll) family of
transcription factors had also reached similar conclusions because Dll homologs are expressed in appendages/body wall outgrowths from phyla as diverse as echinoderms (tube feet)
and annelids (antennae) as well as vertebrate and fly legs. Thus, a common feature of appendage/body wall outgrowths in animals may be a coupling of Dll and RTK signaling.
An understanding of how humans develop is crucial to understanding the causes of various birth defects and our understanding of human development has relied heavily upon
studies originally carried out in Drosophila. It is hoped that studies on RTK signaling in Drosophila leg development may yield novel insights into how
FGFs regulate limb development in vertebrates and how aberrations in this process can lead to limb abnormalities. To this end, these studies in the Campbell lab are being supported by
a grant from the March of Dimes Foundation for Birth Defects.
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