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Identification of Genes Controlling Malpighian Tubule and Other

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Identification of Genes Controlling Malpighian Tubule and Other Copyright 1999 by the Genetics Society of America Identi®cation of Genes Controlling Malpighian Tubule and Other Epithelial Morphogenesis in Drosophila melanogaster Xuejun Liu,* IstvaÂn Kiss² and Judith A. Lengyel* *Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California 90095 and ²Institute of Genetics, Biological Research Center of the Hungarian Academy of Sciences, H-6701, Szeged, Hungary Manuscript received August 21, 1998 Accepted for publication October 26, 1998 ABSTRACT The Drosophila Malpighian tubule is a model system for studying genetic mechanisms that control epithelial morphogenesis. From a screen of 1800 second chromosome lethal lines, by observing uric acid deposits in un®xed inviable embryos, we identi®ed ®ve previously described genes (barr, fas, ¯b, raw, and thr) and one novel gene, walrus (wal), that affect Malpighian tubule morphogenesis. Phenotypic analysis of these mutant embryos allows us to place these genes, along with other previously described genes, into a genetic pathway that controls Malpighian tubule development. Speci®cally, wal affects evagination of the Malpighian tubule buds, fas and thr affect bud extension, and barr, ¯b, raw, and thr affect tubule elongation. In addition, these genes were found to have different effects on development of other epithelial structures, such as foregut and hindgut morphogenesis. Finally, from the same screen, we identi®ed a second novel gene, drumstick, that affects only foregut and hindgut morphogenesis. HILE the importance of epithelial morphogene- ered epithelium (the hindgut primordium, or procto- W sis in development is widely recognized, relatively deum), do not become invested with a mesenchyme, little is known about its molecular basis. A few molecules, and cease cell division relatively early in their develop- for example, members of the Rho GTPase family, have ment. The fully developed organ consists of only two been identi®ed that modulate the cytoskeleton and con- morphologically distinct cell types and comprises a sin- trol cell shape change in culture (reviewed by Hall gle layered epithelial tube with proximal and distal por- 1998). Function of these molecules in vivo has been tions. demonstrated in Drosophila embryogenesis: inactiva- As outlined in Figure 5, the Malpighian tubules arise tion of Rho disrupts gastrulation (HaÈcker and Perri- from the proctodeum. Overlapping expression of the mon 1998), while inactivation of Rac disrupts dorsal tailless (tll), huckebein (hkb), fork head (fkh), and wingless closure (reviewed by Noselli 1998). In addition to these (wg) genes at the posterior of the embryo is required molecules, additional components essential for the epi- to establish and maintain the portion of the proctodeum thelial morphogenetic processes of gastrulation, dorsal from which the tubules arise (Weigel et al. 1989; Gaul closure, and tracheal tube fusion and branching have and Weigel 1990; Skaer 1993; Harbecke and Lengyel been identi®ed in genetic screens and characterized 1995; Wu and Lengyel 1998). Expression of KruÈppel molecularly in Drosophila (reviewed by Leptin 1995; (Kr) in the tubule anlage is required for the tubules to Skaer 1997; Hacohen et al. 1998; Noselli 1998). It bud out from the proctodeum (Harbecke and Janning seems likely, however, that more molecules required 1989; Skaer 1993). Expression of cut in a ring of cells to establish epithelia and to control the proliferation, at the future anteriormost region of the proctodeum is shape, and rearrangement of the cells within epithelia required for extension of the buds. All of the aforemen- remain to be identi®ed. tioned genes required for early development of the tu- The Malpighian tubules of the Drosophila embryo bules, with the exception of wg, encode transcription provide a useful system for investigating the genetics of factors. epithelial morphogenesis. First, the genetic hierarchy In addition to the transcriptional regulation that de- required to establish the tubule primordia and to con- ®nes the tubule primordia and controls early events of trol their early morphogenesis has been partially eluci- tubule development, cell signaling plays an important dated. Second, the tubules constitute one of the simplest role in later steps of tubule development. Hedgehog is possible epithelial organs. As reviewed by Skaer (1993), required for the completion of bud evagination (Hoch the tubules develop as outbuddings from a single lay- and Pankratz 1996), while Wingless is required for cell division and morphogenesis in the tubules (Skaer and Martinez Arias 1992; Harbecke and Lengyel 1995). Corresponding author: Judith A. Lengyel, Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Signaling via the Notch receptor is required to de®ne CA 90095-1606. E-mail: [email protected] the single tip cell at the end of each tubule (Hoch et Genetics 151: 685±695 (February 1999) 686 X. Liu, I. Kiss and J. A. Lengyel al. 1994), which leads out the elongation of the tubule ucts Corporation) to render the chorion transparent and ex- (Skaer 1989). Finally, signaling from the tip cell via an amined at 803 by transmitted light in a dissecting microscope. Consistent with previous analyses (NuÈsslein-Volhard et al. EGF-like ligand is required for the proliferation of the 1984), we found that z30% of the lethal lines were embryonic distal cells of the tubule (Baumann and Skaer 1993; lethal. Forty-three embryonic lethal lines were identi®ed from Kerber et al. 1998). this screen with apparent defective Malpighian tubules and/ To identify additional genes involved in the formation or midgut and examined in more detail by antibody staining and/or morphogenesis of the Malpighian tubules, par- (see below). Antibody staining and phenotypic analysis: Antibody stain- ticularly genes that might regulate the cellular basis of ing was performed using standard protocols (Ashburner morphogenesis (i.e., cell communication, cytoskeleton, 1989). The monoclonal anti-Crb antibody, a generous gift of cell junctions, and polarity), we screened a collection Elisabeth Knust (Tepaû et al. 1990), was used at a dilution of lethal lines carrying P-element insertion(s) on the of 1:100 to label the apical surface of ectodermally derived second chromosome (ToÈroÈk et al. 1993). We identi®ed epithelia. The monoclonal anti-Cut antibody, kindly provided by Karen Blochlinger (Blochlinger et al. 1990), was used at and mapped seven embryonic lethal alleles, falling into a dilution of 1:20 to label the nuclei of Malpighian tubule cells. six complementation groups (loci), that cause Malpigh- The monoclonal anti-Connectin antibody, kindly provided by ian tubule defects. Five of these loci correspond to the Robert White (Meadows et al. 1994), was used at a dilution previously described genes barren (barr), faint sausage of 1:30 to label the visceral mesoderm that ensheathes the (fas), faint little ball (¯b), raw, and three rows (thr). One hindgut and foregut. Whole-mount embryos after antibody staining were analyzed with a Zeiss (Thornwood, NY) Axiophot locus corresponds to a newly identi®ed gene, walrus microscope equipped with differential interference contrast (wal). Phenotypic analysis of these mutants revealed a optics. Of the 43 putative gut defect lines obtained in the number of genetically distinguishable morphogenetic screen, 8 were found by staining with anti-Crb and anti-Cut events required for Malpighian tubule development. In to have defective Malpighian tubules or other gut defects. For addition, these genes were found to be involved in other mutant lines found by complementation to be alleles of known genes (see below), transheterozygous embryos were made by gut epithelial morphogenesis (i.e., proventriculus for- crossing these lines with balanced lethal lines carrying a null mation, hindgut elongation, and midgut constriction), (or the strongest available) allele of the corresponding genes; as well as other morphogenetic processes involving epi- embryos were then stained with various antibodies for detailed thelia, such as germ band retraction, dorsal closure, phenotypic analyses. Embryos were staged according to Cam- head involution, and epidermal differentiation. Finally, pos-Ortega and Hartenstein (1997). Images were acquired by digital camera (Sony, Parkridge, NJ; DKC-5000) using Adobe we have also identi®ed another novel gene, drumstick PhotoShop software. For each ®gure, embryos or portions of (drm), which, in contrast to these genes with global embryos are shown at the same magni®cation. effects, speci®cally affects morphogenesis of hindgut Genetic analysis: Information on the localization of the P and foregut. element(s) in the identi®ed lines was obtained from the Berke- ley Drosophila Genome Center. The de®ciency ªkitº for the second chromosome from the Bloomington Drosophila Stock Center was used to localize a number of the lethal mutations MATERIALS AND METHODS from the screen. In addition, two multiply marked second Fly stocks: We screened the collection of lethal lines with chromosomes, S Sp Tft N-2G Pu and al dp b pr c px sp, were used P-element insertion(s) on the second chromosome described for meiotic mapping of alleles of wal and drm, respectively. by ToÈroÈk et al. (1993). Alleles of ¯b IK35, raw1, thr 1, l(2)02516, Revertant chromosomes were generated from line k14036 and the de®ciency ªkitº for the second chromosome were (wal)byP-element excision as described by ToÈroÈk et al. obtained from the Bloomington
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