THE TORSO AND SEVENLESS PATHWAYS IN DROSOPHILA - A MODEL SYSTEM FOR CELLULAR SIGNALISATION BY TYROSINE-KINASE RECEPTORS

Comparative studies of signal transduction in vertebrates and inverteb rates have revealed a universal inter mediate signalling pathway betwe en specific membrane tyrosine-kinase receptors (TKRs) and their downst ream nuclear effecters. In Drosophila, powerful genetic techniques hav e enabled the identification and characterisation of the members of tw o TKR systems: the activation of the Torso receptor which triggers a c ascade of kinase-related phosphorylations driving nuclear targets to d irect specification of embryonic termini; and tile Sevenless TKR which acts through the same intermediates to induce the differentiation of a specific photoreceptor cell (R7) in the eye ommatidium. Initially, m utant screens based on loss-of-function phenotypes (no embryonic ends, no R7 cell) succeeded in capturing those genes functioning only at th e extremes of the signal chain - at the membrane (receptors, ligands a nd ligand-specific activators) and nuclear (transcription factors) lev els. To isolate intermediate pathway members, common to multiple vital processes, screens were devised in which mutations altering the dosag e of these gene products to sub-lethal levels nonetheless enhanced (en hancer mutations) or suppressed (suppressor mutations) phenotypes asso ciated with mutated forms of Torso or Sevenless receptor partners. Onc e isolated, these loss-of-function and Pain-of-function mutations are combined in the same animal to determine the order of gene functions. Furthermore, clones of homozygous mutant cells can be generated in het erozygous animals to pinpoint in vivo sites of action. Finally, the ab ility to introduce genes that have been mutagenised in vitro into fly embryos provides the ultimate test for hypotheses derived from genetic , biochemical and molecular biological analyses. Through these strateg ies, not only have the now-familiar Ras-MAPK intermediates been identi fied, but some 30-40 potentially new interacting genes have been defin ed, which reveal new aspects of these pathways, their fine regulation and the mechanisms providing the specificity of the cellular response.