9418450 Katz The adult form is built on a scaffold of information laid down in three axes during development: the anterior-posterior, dorsal-ventral, and proximal-distal (PD) axes. The PD axis is used in the formation of the limbs, to set distance from the trunk. When molecules needed to initiate or interpret this axis are abnormal or absent, the limbs fail to form or are grossly distorted in morphology. In the fruit fly, Drosophila melanogaster, we are just beginning to understand how PD axes are established at specific positions in the embryo, but virtually nothing is known about how the individual cells in the developing limb read this axis in order to elaborate segments with different lengths and identities. However, molecules must exist that can respond to this axis, set boundaries, and control growth regionally during limb morphogenesis. The four-jointed (fj) gene appears to have some of the properties expected for molecules involved in these latter events. It is expressed at prospective segment boundaries in the developing leg, its absence results in partial loss and fusion of segments, and it interacts with a group of genes that are required for growth control in the limbs. The molecular characterization of a suggests it encodes a cell surface molecule. The present proposal is concerned with further exploring the biochemical, developmental, and functional properties of this molecule, and revealing the biochemical pathway in which it participates. By looking for interactions with genes that produce similar abnormalities when they are mutant, we have recently shown that mutations in the abelson gene, which can mutate to a cancerous (oncogenic) form in humans, interacts with , fj mutations in Drosophila, suggesting these genes might share a common pathway. Since very little is known about the normal function of the abelson protein, our studies may also contribute to a better understanding of this important molecule. The richness of the genetic interactions already uncovered suggest thes e studies may reveal a new pathway of genes involved in limb development. As it has become apparent that molecules involved in setting the PD axis in flies are also involved in initiating the limb bud in vertebrates, demonstrating a remarkable conservation in strategy and function, molecules involved in the readout and realization of this axis may also be conserved. The exploration of, fj function may therefore not only provide insight into how a fly builds a leg, but may also provide clues to more general and fundamental morphogenetic mechanisms.
