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1.
Genetics ; 178(3): 1399-413, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18245841

ABSTRACT

Signaling by Hedgehog (Hh) proteins shapes most tissues and organs in both vertebrates and invertebrates, and its misregulation has been implicated in many human diseases. Although components of the signaling pathway have been identified, key aspects of the signaling mechanism and downstream targets remain to be elucidated. We performed an enhancer/suppressor screen in Drosophila to identify novel components of the pathway and identified 26 autosomal regions that modify a phenotypic readout of Hh signaling. Three of the regions include genes that contribute constituents to the pathway-patched, engrailed, and hh. One of the other regions includes the gene microtubule star (mts) that encodes a subunit of protein phosphatase 2A. We show that mts is necessary for full activation of Hh signaling. A second region includes the gene second mitotic wave missing (swm). swm is recessive lethal and is predicted to encode an evolutionarily conserved protein with RNA binding and Zn(+) finger domains. Characterization of newly isolated alleles indicates that swm is a negative regulator of Hh signaling and is essential for cell polarity.


Subject(s)
Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Hedgehog Proteins/metabolism , RNA-Binding Proteins/genetics , Signal Transduction , Alleles , Amino Acid Sequence , Animals , Cell Polarity , Cell Size , Chromosomes/metabolism , Drosophila Proteins/chemistry , Drosophila Proteins/metabolism , Drosophila melanogaster/cytology , Drosophila melanogaster/embryology , Embryo, Nonmammalian/metabolism , Genes, Insect , Genes, Suppressor , Larva/metabolism , Molecular Sequence Data , Mutation/genetics , Phenotype , Protein Transport , RNA Interference , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Smoothened Receptor , Wings, Animal/anatomy & histology
2.
Nature ; 437(7058): 560-3, 2005 Sep 22.
Article in English | MEDLINE | ID: mdl-16177792

ABSTRACT

The anterior/posterior (A/P) and dorsal/ventral (D/V) compartment borders that subdivide the wing imaginal discs of Drosophila third instar larvae are each associated with a developmental organizer. Decapentaplegic (Dpp), a member of the transforming growth factor-beta (TGF-beta) superfamily, embodies the activity of the A/P organizer. It is produced at the A/P organizer and distributes in a gradient of decreasing concentration to regulate target genes, functioning non-autonomously to regulate growth and patterning of both the anterior and posterior compartments. Wingless (Wg) is produced at the D/V organizer and embodies its activity. The mechanisms that distribute Dpp and Wg are not known, but proposed mechanisms include extracellular diffusion, successive transfers between neighbouring cells, vesicle-mediated movement, and direct transfer via cytonemes. Cytonemes are actin-based filopodial extensions that have been found to orient towards the A/P organizer from outlying cells. Here we show that in the wing disc, cytonemes orient towards both the A/P and D/V organizers, and that their presence and orientation correlates with Dpp signalling. We also show that the Dpp receptor, Thickveins (Tkv), is present in punctae that move along cytonemes. These observations are consistent with a role for cytonemes in signal transduction.


Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Pseudopodia/metabolism , Wings, Animal/cytology , Wings, Animal/growth & development , Actins/metabolism , Animals , Body Patterning , Drosophila melanogaster/cytology , Drosophila melanogaster/metabolism , Larva/growth & development , Protein Serine-Threonine Kinases/metabolism , Receptors, Cell Surface/metabolism , Signal Transduction , Wings, Animal/metabolism
3.
Mech Dev ; 120(10): 1139-51, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14568103

ABSTRACT

The elucidation of pathways linking patterning to morphogenesis is a problem of great interest. We show here that, in addition to their roles in patterning and morphogenesis of the hindgut, the Drosophila genes drumstick (drm) and bowl are required in the foregut for spatially localized gene expression and the morphogenetic processes that form the proventriculus. drm and bowl belong to a family of genes encoding C(2)H(2) zinc finger proteins; the other two members of this family are odd-skipped (odd) and sob. In both the fore- and hindgut, drm acts upstream of lines (lin), which encodes a putative transcriptional regulator, and relieves its repressive function. In spite of its phenotypic similarities with drm, bowl was found in both foregut and hindgut to act downstream, rather than upstream, of lin. These results support a hierarchy in which Drm relieves the repressive effect of Lin on Bowl, and Bowl then acts to promote spatially localized expression of genes (particularly the JAK/STAT pathway ligand encoded by upd) that control fore- and hindgut morphogenesis. Since the odd-family and lin are conserved in mosquito, mouse, and humans, we propose that the odd-family genes and lin may also interact to control patterning and morphogenesis in other insects and in vertebrates.


Subject(s)
Body Patterning/physiology , Carrier Proteins/genetics , DNA-Binding Proteins/genetics , Drosophila Proteins/genetics , Transcription Factors/genetics , Animals , Body Patterning/genetics , Carrier Proteins/metabolism , DNA-Binding Proteins/metabolism , Digestive System/embryology , Digestive System/metabolism , Drosophila/embryology , Drosophila/genetics , Drosophila/metabolism , Drosophila Proteins/metabolism , Evolution, Molecular , Transcription Factors/metabolism
4.
Development ; 130(1): 135-45, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12441298

ABSTRACT

Rearrangement of cells constrained within an epithelium is a key process that contributes to tubular morphogenesis. We show that activation in a gradient of the highly conserved JAK/STAT pathway is essential for orienting the cell rearrangement that drives elongation of a genetically tractable model. Using loss-of-function and gain-of-function experiments, we show that the components of the pathway from ligand to the activated transcriptional regulator STAT are required for cell rearrangement in the Drosophila embryonic hindgut. The difference in effect between localized expression of ligand (Unpaired) and dominant active JAK (Hopscotch) demonstrates that the ligand plays a cell non-autonomous role in hindgut cell rearrangement. Taken together with the appearance of STAT92E in a gradient in the hindgut epithelium, these results support a model in which an anteroposterior gradient of ligand results in a gradient of activated STAT. These results provide the first example in which JAK/STAT signaling plays a required role in orienting cell rearrangement that elongates an epithelium.


Subject(s)
DNA-Binding Proteins/metabolism , Digestive System/cytology , Digestive System/embryology , Drosophila Proteins/metabolism , Drosophila melanogaster/embryology , Membrane Proteins , Protein-Tyrosine Kinases/metabolism , Trans-Activators/metabolism , Transcription Factors , Animals , Body Patterning/genetics , Carrier Proteins/genetics , Carrier Proteins/metabolism , DNA-Binding Proteins/genetics , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Embryo, Nonmammalian , Embryonic Induction/physiology , Epithelial Cells/metabolism , Epithelium/embryology , Epithelium/metabolism , Gene Expression Regulation, Developmental , Glycoproteins/genetics , Glycoproteins/metabolism , Intestine, Large/cytology , Intestine, Large/embryology , Intestine, Large/metabolism , Janus Kinases , Mutation , Protein-Tyrosine Kinases/genetics , Receptors, Interleukin/genetics , Receptors, Interleukin/metabolism , STAT Transcription Factors , Signal Transduction , Trans-Activators/genetics
5.
Mech Dev ; 114(1-2): 71-84, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12175491

ABSTRACT

The Drosophila hindgut develops three morphologically distinct regions along its anteroposterior axis: small intestine, large intestine and rectum. Single-cell rings of 'boundary cells' delimit the large intestine from the small intestine at the anterior, and the rectum at the posterior. The large intestine also forms distinct dorsal and ventral regions; these are separated by two single-cell rows of boundary cells. Boundary cells are distinguished by their elongated morphology, high level of both apical and cytoplasmic Crb protein, and gene expression program. During embryogenesis, the boundary cell rows arise at the juxtaposition of a domain of Engrailed (En)- plus Invected (Inv)-expressing cells with a domain of Delta (Dl)-expressing cells. Analysis of loss-of-function and ectopic expression phenotypes shows that the domain of Dl-expressing cells is defined by En/Inv repression. Further, Notch pathway signaling, specifically the juxtaposition of Dl-expressing and Dl-non-expressing cells, is required to specify the rows of boundary cells. This Notch-induced cell specification is distinguished by the fact that it does not appear to utilize the ligand Serrate and the modulator Fringe.


Subject(s)
Drosophila/metabolism , Gene Expression Regulation, Developmental , Homeodomain Proteins/metabolism , Membrane Proteins/metabolism , Signal Transduction , Transcription Factors/metabolism , Animals , Body Patterning , Cytoplasm , Drosophila Proteins/metabolism , Intestines/embryology , Intracellular Signaling Peptides and Proteins , Microscopy, Fluorescence , Models, Biological , Phenotype , Receptors, Notch , Rectum/embryology
6.
Dev Biol ; 243(1): 1-19, 2002 Mar 01.
Article in English | MEDLINE | ID: mdl-11846473

ABSTRACT

The Drosophila hindgut is fruitful territory for investigation of events common to many types of organogenesis. The development of the Drosophila hindgut provides, in microcosm, a genetic model system for studying processes such as establishment (patterning) of an epithelial primordium, its internalization by gastrulation, development of left--right asymmetric looping, patterning in both the anteroposterior and dorsoventral axes, innervation, investment of an epithelium with mesoderm, reciprocal epitheliomesenchymal interactions, cell shape change, and cell rearrangement. We review the genetic control of these processes during development of the Drosophila hindgut, and compare these to related processes in other bilaterians, particularly vertebrates. We propose that caudal/Cdx, brachyenteron/Brachyury, fork head/HNF-3, and wingless/Wnt constitute a conserved "cassette" of genes expressed in the blastopore and later in the gut, involved in posterior patterning, cell rearrangement, and gut maintenance. Elongation of the internalized Drosophila hindgut primordium is similar to elongation of the archenteron and also of the entire embryonic axis (both during and after gastrulation), as well as of various tubules (e.g., nephric ducts, Malpighian tubules), as it is driven by cell rearrangement. The genes drumstick, bowl, and lines (which encode putative transcriptional regulators) are required for this cell rearrangement, as well as for spatially localized gene expression required to establish the three morphologically distinct subregions of the hindgut. Expression of signaling molecules regulated by drumstick, bowl, and lines, in particular of the JAK/STAT activator Unpaired at the hindgut anterior, may play a role in controlling hindgut cell rearrangement. Other cell signaling molecules expressed in the hindgut epithelium are required to establish its normal size (Dpp and Hh), and to establish and maintain the hindgut visceral mesoderm (Wg and Hh). Both maternal gene activity and zygotic gene activity are required for asymmetric left--right looping of the hindgut. Some of the same genes (caudal and brachyenteron) required for embryonic hindgut development also act during pupation to construct a new hindgut from imaginal cells. Application of the plethora of genetic techniques available in Drosophila, including forward genetic screens, should identify additional genes controlling hindgut development and thus shed light on a variety of common morphogenetic processes.


Subject(s)
Body Patterning , Digestive System/embryology , Drosophila/embryology , Drosophila/genetics , Animals , Embryo, Nonmammalian/physiology , Embryonic Induction , Gastrula/physiology , Gene Expression Regulation, Developmental
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