GENES CONTROLLING GUT MORPHOGENESIS

我们现在有能力研究分子/基因

We are now in the position to be able to study molecular/genetic pathways controlling morphogenesis. Certain processes of morphogenesis, particularly convergent extension, which cells intercalate between each other to generate a longer, narrower structure, are common to many crucial events in development, such as gastrulation and tubulogenesis. The generality of these processes, as well as the numerous homologies recently discovered between Drosophila and vertebrate genes, virtually assures that genes controlling morphogenesis discovered and analyzed in the model organism Drosophila will have vertebrate homologs. Development of the posterior gut provides an excellent entree into the problem of convergent extension, since this process occurs in the Drosophila embryo after cell proliferation has already occurred, and at least for the hindgut, without the complicating factor of interaction with mesoderm. Additionally, earlier work from our and other laboratories on embryonic patterning has already characterized the early transcription factor hierarchy that establishes the gut primordia. By screening for mutants affecting posterior gut development, we have identified the arc gene, which controls convergent extension in the Malpighian tubules, and the drm gene, which controls elongation of the hindgut. The Arc protein contains a single PDZ domain and appears to associate with the apical membrane surface. We will characterize Arc function by localizing it in more detail, and determining what proteins it interacts with. We will look for Arc-related proteins in Drosophila and vertebrates to see if they play similar roles in morphogesis. We will carry out a molecular characterization of drm, to determine its expression pattern, and the molecular properties and cellular location of the Drm protein. Using genetic screens, we will identify additional previously undescribed genes that play a role in posterior gut morphogenesis. We will characterize phenotypes of all of these genes in more detail (including at the electron microscope level). We will use these data to generate a model for the genetic basis of convergent extension morphogenesis in gut tubules. Characterization of the Drosophila arc, drm and other genes will assist in identifying vertebrate genes controlling morphogenesis; defects in these vertebrate cognates are likely to contribute to human birth defects.