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  1. Miura GI, Roignant JY, Wassef M, Treisman JE. "Myopic acts in the endocytic pathway to enhance signaling by the Drosophila EGF receptor," Development 2008 Apr 23;.   (MEDL:18434417 PMID: 18434417 #J0136988)    

    Endocytosis of activated receptors can control signaling levels by exposing the receptors to novel downstream molecules or by instigating their degradation. Epidermal growth factor receptor (EGFR) signaling has crucial roles in development and is misregulated in many cancers. We report here that Myopic, the Drosophila homolog of the Bro1-domain tyrosine phosphatase HD-PTP, promotes EGFR signaling in vivo and in cultured cells. myopic is not required in the presence of activated Ras or in the absence of the ubiquitin ligase Cbl, indicating that it acts on internalized EGFR, and its overexpression enhances the activity of an activated form of EGFR. Myopic is localized to intracellular vesicles adjacent to Rab5-containing early endosomes, and its absence results in the enlargement of endosomal compartments. Loss of Myopic prevents cleavage of the EGFR cytoplasmic domain, a process controlled by the endocytic regulators Cbl and Sprouty. We suggest that Myopic promotes EGFR signaling by mediating its progression through the endocytic pathway.

  2. Hofmeyer, K, Maurel-Zaffran, C, Treisman, J. "Liprin-alpha acts both downstream of and in parallel to lar in R7 photoreceptor axon targeting [Abstract]," Journal of neurogenetics 2006 JUL-DEC;20(3-4):130-131.   (ISI:000243309500084 #J0124946)    

  3. Hofmeyer, Kerstin, Maurel-Zaffran, Corinne, Sink, Helen, Treisman, Jessica E. "Liprin-alpha has LAR-independent functions in R7 photoreceptor axon targeting," Proceedings of the National Academy of Sciences of the United States of America 2006 Aug 1;103(31):11595-600. Epub 2006 Jul 24.   (MEDL:16864797 PMID: 16864797 #J0121132)    

    In the Drosophila visual system, the color-sensing photoreceptors R7 and R8 project their axons to two distinct layers in the medulla. Loss of the receptor tyrosine phosphatase LAR from R7 photoreceptors causes their axons to terminate prematurely in the R8 layer. Here we identify a null mutation in the Liprin-alpha gene based on a similar R7 projection defect. Liprin-alpha physically interacts with the inactive D2 phosphatase domain of LAR, and this domain is also essential for R7 targeting. However, another LAR-dependent function, egg elongation, requires neither Liprin-alpha nor the LAR D2 domain. Although human and Caenorhabditis elegans Liprin-alpha proteins have been reported to control the localization of LAR, we find that LAR localizes to focal adhesions in Drosophila S2R+ cells and to photoreceptor growth cones in vivo independently of Liprin-alpha. In addition, Liprin-alpha overexpression or loss of function can affect R7 targeting in the complete absence of LAR. We conclude that Liprin-alpha does not simply act by regulating LAR localization but also has LAR-independent functions.

  4. Janody, F, Treisman, JE. "Actin Capping protein alpha maintains vestigial-expressing cells within the Drosophila wing disc epithelium," Development 2006 SEP 1;133(17):3349-3357.   (ISI:000239758700008 #J0119498)    

    Tissue patterning must be translated into morphogenesis through cell shape changes mediated by remodeling of the actin cytoskeleton. We have found that Capping protein alpha (Cpa) and Capping protein beta (Cpb), which prevent extension of the barbed ends of actin filaments, are specifically required in the wing blade primordium of the Drosophila wing disc. cpa or cpb mutant cells in this region, but not in the remainder of the wing disc, are extruded from the epithelium and undergo apoptosis. Excessive actin filament polymerization is not sufficient to explain this phenotype, as loss of Cofilin or Cyclase-associated protein does not cause cell extrusion or death. Misexpression of Vestigial, the transcription factor that specifies the wing blade, both increases cpa transcription and makes cells dependent on cpa for their maintenance in the epithelium. Our results suggest that Vestigial specifies the cytoskeletal changes that lead to morphogenesis of the adult wing.

  5. Miura, Grant I, Treisman, Jessica E. "Lipid modification of secreted signaling proteins," Cell cycle 2006 Jun;5(11):1184-8. Epub 2006 Jun 1.   (MEDL:16721064 PMID: 16721064 #J0119053)    

    Proteins of the Hedgehog, Wnt and Epidermal Growth Factor Receptor (EGFR) ligand families are secreted signals that induce concentration-dependent responses in surrounding cells. Although these proteins must diffuse through the aqueous extracellular environment, recent work has shown that hydrophobic lipid modifications are essential for their functions. All three classes of ligands are palmitoylated in the secretory pathway by related enzymes, and Hedgehog also carries a C-terminal cholesterol modification as a result of its autocatalytic cleavage. Palmitoylation is required for Wingless secretion and contributes to the signaling activity of Hedgehog and Wnt3a, but is not required for secretion or receptor activation by the EGFR ligand Spitz. While lipid modifications enhance the long-range activity of Sonic hedgehog, they restrict the range and increase the local concentration of Spitz. We discuss the diverse functions and the possible extent of palmitoylation of secreted ligands.

  6. Miura GI, Buglino J, Alvarado D, Lemmon MA, Resh MD, Treisman JE. "Palmitoylation of the EGFR ligand Spitz by Rasp increases Spitz activity by restricting its diffusion," Developmental cell 2006 Feb;10(2):167-76.   (MEDL:16459296 PMID: 16459296 #J0112999)    

    Lipid modifications such as palmitoylation or myristoylation target intracellular proteins to cell membranes. Secreted ligands of the Hedgehog and Wnt families are also palmitoylated; this modification, which requires the related transmembrane acyltransferases Rasp and Porcupine, can enhance their secretion, transport, or activity. We show here that rasp is also essential for the developmental functions of Spitz, a ligand for the Drosophila epidermal growth factor receptor (EGFR). In cultured cells, Rasp promotes palmitate addition to the N-terminal cysteine residue of Spitz, and this cysteine is required for Spitz activity in vivo. Palmitoylation reduces Spitz secretion and enhances its plasma membrane association, but does not alter its ability to activate the EGFR in vitro. In vivo, overexpressed unpalmitoylated Spitz has an increased range of action but reduced activity. These data suggest a role for palmitoylation in restricting Spitz diffusion, allowing its local concentration to reach the threshold required for biological function.

  7. Roignant JY, Hamel S, Janody F, Treisman JE. "The novel SAM domain protein Aveugle is required for Raf activation in the Drosophila EGF receptor signaling pathway," Genes & development 2006 Apr 1;20(7):795-806.   (MEDL:16600911 PMID: 16600911 #J0114483)    

    Activation of the Raf kinase by GTP-bound Ras is a poorly understood step in receptor tyrosine kinase signaling pathways. One such pathway, the epidermal growth factor receptor (EGFR) pathway, is critical for cell differentiation, survival, and cell cycle regulation in many systems, including the Drosophila eye. We have identified a mutation in a novel gene, aveugle, based on its requirement for normal photoreceptor differentiation. The phenotypes of aveugle mutant cells in the eye and wing imaginal discs resemble those caused by reduction of EGFR pathway function. We show that aveugle is required between ras and raf for EGFR signaling in the eye and for mitogen-activated protein kinase phosphorylation in cell culture. aveugle encodes a small protein with a sterile alpha motif (SAM) domain that can physically interact with the scaffold protein connector enhancer of Ksr (Cnk). We propose that Aveugle acts together with Cnk to promote Raf activation, perhaps by recruiting an activating kinase.

  8. Janody F, Lee JD, Jahren N, Hazelett DJ, Benlali A, Miura GI, Draskovic I, Treisman JE. "A mosaic genetic screen reveals distinct roles for trithorax and polycomb group genes in Drosophila eye development," Genetics 2004 Jan;166(1):187-200.   (MEDL:15020417 PMID: 15020417 #J0067842)    

    The wave of differentiation that traverses the Drosophila eye disc requires rapid transitions in gene expression that are controlled by a number of signaling molecules also required in other developmental processes. We have used a mosaic genetic screen to systematically identify autosomal genes required for the normal pattern of photoreceptor differentiation, independent of their requirements for viability. In addition to genes known to be important for eye development and to known and novel components of the Hedgehog, Decapentaplegic, Wingless, Epidermal growth factor receptor, and Notch signaling pathways, we identified several members of the Polycomb and trithorax classes of genes encoding general transcriptional regulators. Mutations in these genes disrupt the transitions between zones along the anterior-posterior axis of the eye disc that express different combinations of transcription factors. Different trithorax group genes have very different mutant phenotypes, indicating that target genes differ in their requirements for chromatin remodeling, histone modification, and coactivation factors.

  9. Lee A, Treisman JE. "Excessive Myosin activity in mbs mutants causes photoreceptor movement out of the Drosophila eye disc epithelium," Molecular biology of the cell 2004 Jul;15(7):3285-95. Epub 2004 Apr 9.   (MEDL:15075368 PMID: 15075368 #J0067843)    

    Neuronal cells must extend a motile growth cone while maintaining the cell body in its original position. In migrating cells, myosin contraction provides the driving force that pulls the rear of the cell toward the leading edge. We have characterized the function of myosin light chain phosphatase, which down-regulates myosin activity, in Drosophila photoreceptor neurons. Mutations in the gene encoding the myosin binding subunit of this enzyme cause photoreceptors to drop out of the eye disc epithelium and move toward and through the optic stalk. We show that this phenotype is due to excessive phosphorylation of the myosin regulatory light chain Spaghetti squash rather than another potential substrate, Moesin, and that it requires the nonmuscle myosin II heavy chain Zipper. Myosin binding subunit mutant cells continue to express apical epithelial markers and do not undergo ectopic apical constriction. In addition, mutant cells in the wing disc remain within the epithelium and differentiate abnormal wing hairs. We suggest that excessive myosin activity in photoreceptor neurons may pull the cell bodies toward the growth cones in a process resembling normal cell migration.

  10. Ma J, Plesken H, Treisman JE, Edelman-Novemsky I, Ren M. "Lightoid and Claret: a rab GTPase and its putative guanine nucleotide exchange factor in biogenesis of Drosophila eye pigment granules," Proceedings of the National Academy of Sciences of the United States of America 2004 Aug 10;101(32):11652-7. Epub 2004 Aug 02.   (MEDL:15289618 PMID: 15289618 #J0070251)    

    To elucidate the biogenetic pathways for the generation of lysosome-related organelles, we have chosen to study the Drosophila eye pigment granules because they are lysosome-related and the fruit fly provides the advantages of a genetic system in which many mutations affect eye color. Here, we report the molecular identification of two classic Drosophila eye-color genes required for pigment granule biogenesis, claret and lightoid; the former encodes a protein containing seven repeats with sequence similarity to those that characterize regulator of chromosome condensation 1 (RCC1, a guanine nucleotide exchange factor for the small GTPase, Ran), and the latter encodes a rab GTPase, Rab-RP1. We demonstrate in transfected cells that Claret, through its RCC1-like domain, interacts preferentially with the nucleotide-free form of Rab-RP1, and this interaction involves Claret's first three RCC1-like repeats that are also critical for Claret's function in pigment granule biogenesis in transgenic rescue experiments. In addition, double-mutant analyses suggest that the gene products of claret and lightoid function in the same pathway, which is different from that of garnet and ruby (which encode the delta- and beta-subunit of the tetrameric adaptor protein 3 complex, respectively). Taken together, our results suggest that Claret functions as a guanine nucleotide exchange factor for Lightoid/Rab-RP1 in an adaptor protein 3-independent vesicular trafficking pathway of pigment granule biogenesis.

  11. Treisman JE. "Coming to our senses," Bioessays 2004 Aug;26(8):825-8.   (MEDL:15273984 PMID: 15273984 #J0070253)    

    Sensory organs are specialized to receive different kinds of input from the outside world. However, common features of their development suggest that they could have a shared evolutionary origin. In a recent paper, Niwa et al. show that three Drosophila adult sensory organs all rely on the spatial signals Decapentaplegic and Wingless to specify their position, and the temporal signal ecdysone to initiate their development. The proneural gene atonal is an important site for integration of these regulatory inputs. These results suggest the existence of a primitive sensory organ precursor, which would differentiate according to the identity of its segment of origin. The authors argue that the eyeless gene controls eye disc identity, indirectly producing an eye from the sensory organ precursor within this disc.

  12. Treisman JE. "How to make an eye," Development 2004 Aug;131(16):3823-7.   (MEDL:15289432 PMID: 15289432 #J0070252)    

    The eye is an organ of such remarkable complexity and apparently flawless design that it presents a challenge to both evolutionary biologists trying to explain its phylogenetic origins, and developmental biologists hoping to understand its formation during ontogeny. Since the discovery that the transcription factor Pax6 plays a crucial role in specifying the eye throughout the animal kingdom, both groups of biologists have been converging on the conserved mechanisms behind eye formation. Their latest meeting was at the Instituto Juan March in Madrid, at a workshop organized by Walter Gehring (Biozentrum, Basel, Switzerland) and Emili Salo (Universitat de Barcelona, Spain), entitled 'The genetic control of eye development and its evolutionary implications'. The exchange of ideas provided some new insights into the construction and history of the eye.

  13. Janody F, Martirosyan Z, Benlali A, Treisman JE. "Two subunits of the Drosophila mediator complex act together to control cell affinity," Development 2003 Aug;130(16):3691-701.   (MEDL:22719038 PMID: 12835386 #J0051854)    

    The organizing centers for Drosophila imaginal disc development are created at straight boundaries between compartments; these are maintained by differences in cell affinity controlled by selector genes and intercellular signals. skuld and kohtalo encode homologs of TRAP240 and TRAP230, the two largest subunits of the Drosophila mediator complex; mutations in either gene cause identical phenotypes. We show here that both genes are required to establish normal cell affinity differences at the anterior-posterior and dorsal-ventral compartment boundaries of the wing disc. Mutant cells cross from the anterior to the posterior compartment, and can distort the dorsal-ventral boundary in either the dorsal or ventral direction. The Skuld and Kohtalo proteins physically interact in vivo and have synergistic effects when overexpressed, consistent with a skuld kohtalo double-mutant phenotype that is indistinguishable from either single mutant. We suggest that these two subunits do not participate in all of the activities of the mediator complex, but form a submodule that is required to regulate specific target genes, including those that control cell affinity.

  14. Miura, GI, Lee, JD, Treisman, JE. "Sightless encodes a transmembrane acyltransferase required for hedgehog signaling [Abstract]," Developmental biology (Orlando) 2003 JUL 15;259(2):460-460.   (ISI:000184373300077 #J0101907)    

  15. Lee JD, Amanai K, Shearn A, Treisman JE. "The ubiquitin ligase Hyperplastic discs negatively regulates hedgehog and decapentaplegic expression by independent mechanisms," Development 2002 Dec 15;129(24):5697-5706.   (MEDL:0 PMID: 12421709 #J0045550) Full Text Link!   

    Photoreceptor differentiation in the Drosophila eye disc progresses from posterior to anterior in a wave driven by the Hedgehog and Decapentaplegic signals. Cells mutant for the hyperplastic discs gene misexpress both of these signaling molecules in anterior regions of the disc, leading to premature photoreceptor differentiation and overgrowth of surrounding tissue. The two genes are independently regulated by hyperplastic discs; decapentaplegic can still be misexpressed in cells mutant for both hyperplastic discs and hedgehog, and a repressor form of the transcription factor Cubitus interruptus can block decapentaplegic misexpression but not hedgehog misexpression. Loss of hyperplastic discs causes the accumulation of full-length Cubitus interruptus protein, but not of Smoothened, in both the eye and wing discs. hyperplastic discs encodes a HECT domain E3 ubiquitin ligase that is likely to act by targeting Cubitus interruptus and an unknown activator of hedgehog expression for proteolysis.

  16. Treisman J, Lang R. "Development and evolution of the eye: Fondation des Treilles, September, 2001," Mechanisms of development 2002 Mar;112(1-2):3-8.   (MEDL:21839541 PMID: 11850173 #J0044738) Full Text Link!   

  17. Lee JD, Kraus P, Gaiano N, Nery S, Kohtz J, Fishell G, Loomis CA, Treisman JE. "An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development," Developmental biology (Orlando) 2001 May 1;233(1):122-36.   (MEDL:21220785 PMID: 11319862 #J0022631) Full Text Link!   

    The Drosophila Hedgehog protein and its vertebrate counterpart Sonic hedgehog are required for a wide variety of patterning events throughout development. Hedgehog proteins are secreted from cells and undergo autocatalytic cleavage and cholesterol modification to produce a mature signaling domain. This domain of Sonic hedgehog has recently been shown to acquire an N-terminal acyl group in cell culture. We have investigated the in vivo role that such acylation might play in appendage patterning in mouse and Drosophila; in both species Hedgehog proteins define a posterior domain of the limb or wing. A mutant form of Sonic hedgehog that cannot undergo acylation retains significant ability to repattern the mouse limb. However, the corresponding mutation in Drosophila Hedgehog renders it inactive in vivo, although it is normally processed. Furthermore, overexpression of the mutant form has dominant negative effects on Hedgehog signaling. These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appendages differs between species. Copyright 2001 Academic Press.

  18. Lee JD, Treisman JE. "The role of Wingless signaling in establishing the anteroposterior and dorsoventral axes of the eye disc," Development 2001 May;128(9):1519-29.   (MEDL:21185974 PMID: 11290291 #J0022728) Full Text Link!   

    The posteriorly expressed signaling molecules Hedgehog and Decapentaplegic drive photoreceptor differentiation in the Drosophila eye disc, while at the anterior lateral margins Wingless expression blocks ectopic differentiation. We show here that mutations in axin prevent photoreceptor differentiation and lead to tissue overgrowth and that both these effects are due to ectopic activation of the Wingless pathway. In addition, ectopic Wingless signaling causes posterior cells to take on an anterior identity, reorienting the direction of morphogenetic furrow progression in neighboring wild-type cells. We also show that signaling by Decapentaplegic and Hedgehog normally blocks the posterior expression of anterior markers such as Eyeless. Wingless signaling is not required to maintain anterior Eyeless expression and in combination with Decapentaplegic signaling can promote its downregulation, suggesting that additional molecules contribute to anterior identity. Along the dorsoventral axis of the eye disc, Wingless signaling is sufficient to promote dorsal expression of the Iroquois gene mirror, even in the absence of the upstream factor pannier. However, Wingless signaling does not lead to ventral mirror expression, implying the existence of ventral repressors.

  19. Lee JD, Treisman JE. "Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein," Current biology. CB 2001 Jul 24;11(14):1147-52.   (MEDL:21400488 PMID: 11509241 #J0028887) Full Text Link!   

    Proteins of the Hedgehog (Hh) family act as important developmental signals in a variety of species [1]. Hh proteins are synthesized as full-length precursors that are autocatalytically cleaved by their C-terminal domains to release the signaling N-terminal domains [2]. The addition of a cholesterol molecule to the C terminus of the signaling domain is concomitant with cleavage [3]. Vertebrate Sonic hedgehog (Shh) proteins have also been shown to acquire a fatty acid chain on the N-terminal cysteine of this domain [4], which is required for a subset of their in vivo functions [5, 6]. A mutation of the corresponding cysteine in Drosophila Hh transforms it into a dominant-negative protein [6]. We have identified a novel gene, sightless (sit), which is required for the activity of Drosophila Hh in the eye and wing imaginal discs and in embryonic segmentation. sit acts in the cells that produce Hh, but does not affect hh transcription, Hh cleavage, or the accumulation of Hh protein. sit encodes a conserved transmembrane protein with homology to a family of membrane-bound acyltransferases. The Sit protein could act by acylating Hh or by promoting other modifications or trafficking events necessary for its function.

  20. Maurel-Zaffran C, Suzuki T, Gahmon G, Treisman JE, Dickson BJ. "Cell-autonomous and -nonautonomous functions of LAR in R7 photoreceptor axon targeting," Neuron 2001 Oct 25;32(2):225-35.   (MEDL:21542004 PMID: 11683993 #J0028844) Full Text Link!   

    During Drosophila visual system development, photoreceptors R7 and R8 project axons to targets in distinct layers of the optic lobe. We show here that the LAR receptor tyrosine phosphatase is required in the eye for correct targeting of R7 axons. In LAR mutants, R7 axons initially project to their correct target layer, but then retract to the R8 target layer. This targeting defect can be fully rescued by transgenic expression of LAR in R7, and partially rescued by expression of LAR in R8. The phosphatase domains of LAR are required for its activity in R7, but not in R8. These data suggest that LAR can act both as a receptor in R7, and as a ligand provided by R8. Genetic interactions implicate both Enabled and Trio in LAR signal transduction.

  21. Pichaud F, Treisman J, Desplan C. "Reinventing a common strategy for patterning the eye [Comment]," Cell 2001 Apr 6;105(1):9-12.   (MEDL:21197940 PMID: 11300998 #J0022731) Full Text Link!   

  22. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. "The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation," Cell 2001 May 4;105(3):345-55.   (MEDL:21246503 PMID: 11348591 #J0022729) Full Text Link!   

    The inherited human disease tuberous sclerosis, characterized by hamartomatous tumors, results from mutations in either TSC1 or TSC2. We have characterized mutations in the Drosophila Tsc1 and Tsc2/gigas genes. Inactivating mutations in either gene cause an identical phenotype characterized by enhanced growth and increased cell size with no change in ploidy. Overall, mutant cells spend less time in G1. Coexpression of both Tsc1 and Tsc2 restricts tissue growth and reduces cell size and cell proliferation. This phenotype is modulated by manipulations in cyclin levels. In postmitotic mutant cells, levels of Cyclin E and Cyclin A are elevated. This correlates with a tendency for these cells to reenter the cell cycle inappropriately as is observed in the human lesions.

  23. Treisman J. "Drosophila homologues of the transcriptional coactivation complex subunits TRAP240 and TRAP230 are required for identical processes in eye-antennal disc development," Development 2001 Feb;128(4):603-15.   (MEDL:21098949 PMID: 11171343 #J0022730) Full Text Link!   

    We have identified mutations in two genes, blind spot and kohtalo, that encode Drosophila homologues of human TRAP240 and TRAP230, components of a large transcriptional coactivation complex homologous to the yeast Mediator complex. Loss of either blind spot or kohtalo has identical effects on the development of the eye-antennal disc. Eye disc cells mutant for either gene can express decapentaplegic and atonal in response to Hedgehog signaling, but they maintain inappropriate expression of these genes and fail to differentiate further. Mutant cells in the antennal disc lose expression of Distal-less and misexpress eyeless, suggesting a partial transformation towards the eye fate. blind spot and kohtalo are not required for cell proliferation or survival, and their absence cannot be rescued by activation of the Hedgehog or Notch signaling pathways. These novel and specific phenotypes suggest that TRAP240 and TRAP230 act in concert to mediate an unknown developmental signal or a combination of signals.

  24. Benlali A, Draskovic I, Hazelett DJ, Treisman JE. "act up controls actin polymerization to alter cell shape and restrict Hedgehog signaling in the Drosophila eye disc," Cell 2000 Apr 28;101(3):271-81.   (MEDL:20304332 PMID: 10847682 #J0008907) Full Text Link!   

    Cells in the morphogenetic furrow of the Drosophila eye disc undergo a striking shape change immediately prior to their neuronal differentiation. We have isolated mutations in a novel gene, act up (acu), that is required for this shape change. acu encodes a homolog of yeast cyclase-associated protein, which sequesters monomeric actin; we show that acu is required to prevent actin filament polymerization in the eye disc. In contrast, profilin promotes actin filament polymerization, acting epistatically to acu. However, both acu and profilin are required to prevent premature Hedgehog-induced photoreceptor differentiation ahead of the morphogenetic furrow. These findings suggest that dynamic changes in actin filaments alter cell shape to control the movement of signals that coordinate a wave of differentiation.

  25. Collins RT, Treisman JE. "Osa-containing Brahma chromatin remodeling complexes are required for the repression of wingless target genes," Genes & development 2000 Dec 15;14(24):3140-52.   (MEDL:20573925 PMID: 11124806 #J0053715)    

    The Wingless signaling pathway directs many developmental processes in Drosophila by regulating the expression of specific downstream target genes. We report here that the product of the trithorax group gene osa is required to repress such genes in the absence of the Wingless signal. The Wingless-regulated genes nubbin, Distal-less, and decapentaplegic and a minimal enhancer from the Ultrabithorax gene are misexpressed in osa mutants and repressed by ectopic Osa. Osa-mediated repression occurs downstream of the up-regulation of Armadillo but is sensitive both to the relative levels of activating Armadillo/Pangolin and repressing Groucho/Pangolin complexes present and to the responsiveness of the promoter to Wingless. Osa functions as a component of the Brahma chromatin-remodeling complex; other components of this complex are likewise required to repress Wingless target genes. These results suggest that altering the conformation of chromatin is an important mechanism by which Wingless signaling activates gene expression.

  26. Dobens LL, Peterson JS, Treisman J, Raftery LA. "Drosophila bunched integrates opposing DPP and EGF signals to set the operculum boundary," Development 2000 Feb;127(4):745-54.   (MEDL:20115428 PMID: 10648233 #J0031102) Full Text Link!   

    The Drosophila BMP homolog DPP can function as a morphogen, inducing multiple cell fates across a developmental field. However, it is unknown how graded levels of extracellular DPP are interpreted to organize a sharp boundary between different fates. Here we show that opposing DPP and EGF signals set the boundary for an ovarian follicle cell fate. First, DPP regulates gene expression in the follicle cells that will create the operculum of the eggshell. DPP induces expression of the enhancer trap reporter A359 and represses expression of bunched, which encodes a protein similar to the mammalian transcription factor TSC-22. Second, DPP signaling indirectly regulates A359 expression in these cells by downregulating expression of bunched. Reduced bunched function restores A359 expression in cells that lack the Smad protein MAD; ectopic expression of BUNCHED suppresses A359 expression in this region. Importantly, reduction of bunched function leads to an expansion of the operculum and loss of the collar at its boundary. Third, EGF signaling upregulates expression of bunched. We previously demonstrated that the bunched expression pattern requires the EGF receptor ligand GURKEN. Here we show that activated EGF receptor is sufficient to induce ectopic bunched expression. Thus, the balance of DPP and EGF signals sets the boundary of bunched expression. We propose that the juxtaposition of cells with high and low BUNCHED activity organizes a sharp boundary for the operculum fate.

  27. Heberlein U, Treisman JE. "Early retinal development in Drosophila," Results & problems in cell differentation 2000;31:37-50.   (MEDL:10929400 PMID: 10929400 #J0079282)    

  28. Maurel-Zaffran C, Treisman JE. "pannier acts upstream of wingless to direct dorsal eye disc development in Drosophila," Development 2000 Mar;127(5):1007-16.   (MEDL:20129924 PMID: 10662640 #J0009157) Full Text Link!   

    The dorsoventral midline of the Drosophila eye disc is a source of signals that stimulate growth of the eye disc, define the point at which differentiation initiates, and direct ommatidial rotation in opposite directions in the two halves of the eye disc. This boundary region seems to be established by the genes of the iroquois complex, which are expressed in the dorsal half of the disc and inhibit fringe expression there. Fringe controls the activation of Notch and the expression of its ligands, with the result that Notch is activated only at the fringe expression boundary at the midline. The secreted protein Wingless activates the dorsal expression of the iroquois genes. We show here that pannier, which encodes a GATA family transcription factor expressed at the dorsal margin of the eye disc from embryonic stages on, acts upstream of wingless to control mirror and fringe expression and establish the dorsoventral boundary. Loss of pannier function leads to the formation of an ectopic eye field and the reorganization of ommatidial polarity, and ubiquitous pannier expression can abolish the eye field. Pannier is thus the most upstream element yet described in dorsoventral patterning of the eye disc.

  29. Su YC, Maurel-Zaffran C, Treisman JE, Skolnik EY. "The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals," Molecular & cellular biology 2000 Jul;20(13):4736-44.   (MEDL:20307877 PMID: 10848599 #J0008906) Full Text Link!   

    We have previously shown that the Ste20 kinase encoded by misshapen (msn) functions upstream of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase module in Drosophila. msn is required to activate the Drosophila JNK, Basket (Bsk), to promote dorsal closure of the embryo. A mammalian homolog of Msn, Nck interacting kinase, interacts with the SH3 domains of the SH2-SH3 adapter protein Nck. We now show that Msn likewise interacts with Dreadlocks (Dock), the Drosophila homolog of Nck. dock is required for the correct targeting of photoreceptor axons. We have performed a structure-function analysis of Msn in vivo in Drosophila in order to elucidate the mechanism whereby Msn regulates JNK and to determine whether msn, like dock, is required for the correct targeting of photoreceptor axons. We show that Msn requires both a functional kinase and a C-terminal regulatory domain to activate JNK in vivo in Drosophila. A mutation in a PXXP motif on Msn that prevents it from binding to the SH3 domains of Dock does not affect its ability to rescue the dorsal closure defect in msn embryos, suggesting that Dock is not an upstream regulator of msn in dorsal closure. Larvae with only this mutated form of Msn show a marked disruption in photoreceptor axon targeting, implicating an SH3 domain protein in this process; however, an activated form of Msn is not sufficient to rescue the dock mutant phenotype. Mosaic analysis reveals that msn expression is required in photoreceptors in order for their axons to project correctly. The data presented here genetically link msn to two distinct biological events, dorsal closure and photoreceptor axon pathfinding, and thus provide the first evidence that Ste20 kinases of the germinal center kinase family play a role in axonal pathfinding. The ability of Msn to interact with distinct classes of adapter molecules in dorsal closure and photoreceptor axon pathfinding may provide the flexibility that allows it to link to distinct upstream signaling systems.

  30. Collins RT, Furukawa T, Tanese N, Treisman JE. "Osa associates with the Brahma chromatin remodeling complex and promotes the activation of some target genes," EMBO journal 1999 Dec 15;18(24):7029-7040.   (MEDL:20069333 PMID: 10601025 #J0004825) Full Text Link!   

    The yeast SWI/SNF complex and its Drosophila and mammalian homologs are thought to control gene expression by altering chromatin structure, but the mechanism and specificity of this process are not fully understood. The Drosophila osa gene, like yeast SWI1, encodes an AT-rich interaction (ARID) domain protein. We present genetic and biochemical evidence that Osa is a component of the Brahma complex, the Drosophila homolog of SWI/SNF. The ARID domain of Osa binds DNA without sequence specificity in vitro, but it is sufficient to direct transcriptional regulatory domains to specific target genes in vivo. Endogenous Osa appears to promote the activation of some of these genes. We show evidence that some Brahma-containing complexes do not contain Osa and that Osa is not required to localize Brahma to chromatin. These data suggest that Osa modulates the function of the Brahma complex.

  31. Liu H, Su YC, Becker E, Treisman J, Skolnik EY. "A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinase Misshapen and activates Jun kinase," Current biology. CB 1999 Jan 28;9(2):101-4.   (MEDL:99147085 PMID: 10021364 #J0000130) Full Text Link!   

    Two families of protein kinases that are closely related to Ste20 in their kinase domain have been identified - the p21-activated protein kinase (Pak) and SPS1 families [1-3]. In contrast to Pak family members, SPS1 family members do not bind and are not activated by GTP-bound p21Rac and Cdc42. We recently placed a member of the SPS1 family, called Misshapen (Msn), genetically upstream of the c-Jun amino-terminal (JNK) mitogen-activated protein (MAP) kinase module in Drosophila [4]. The failure to activate JNK in Drosophila leads to embryonic lethality due to the failure of these embryos to stimulate dorsal closure [5-8]. Msn probably functions as a MAP kinase kinase kinase kinase in Drosophila, activating the JNK pathway via an, as yet, undefined MAP kinase kinase kinase. We have identified a Drosophila TNF-receptor-associated factor, DTRAF1, by screening for Msn-interacting proteins using the yeast two-hybrid system. In contrast to the mammalian TRAFs that have been shown to activate JNK, DTRAF1 lacks an amino-terminal 'Ring-finger' domain, and overexpression of a truncated DTRAF1, consisting of only its TRAF domain, activates JNK. We also identified another DTRAF, DTRAF2, that contains an amino-terminal Ring-finger domain. Msn specifically binds the TRAF domain of DTRAF1 but not that of DTRAF2. In Drosophila, DTRAF1 is thus a good candidate for an upstream molecule that regulates the JNK pathway by interacting with, and activating, Msn. Consistent with this idea, expression of a dominant-negative Msn mutant protein blocks the activation of JNK by DTRAF1. Furthermore, coexpression of Msn with DTRAF1 leads to the synergistic activation of JNK. We have extended some of these observations to the mammalian homolog of Msn, Nck-interacting kinase (NIK), suggesting that TRAFs also play a critical role in regulating Ste20 kinases in mammals.

  32. Treisman JE. "A conserved blueprint for the eye?," Bioessays 1999 Oct;21(10):843-50.   (MEDL:99428282 PMID: 10497334 #J0009309) Full Text Link!   

    Although the eyes of all organisms have a common function, visual perception, their structures and developmental mechanisms are quite diverse. Recent research on eye development in Drosophila has identified a set of putative transcription factors required for the earliest step of eye development, specification of the field of cells that will give rise to the eye. These factors appear to act in a hierarchy, although cross-regulation may amplify the eye fate decision or promote progression to the next step. Surprisingly, homologous proteins are also involved in vertebrate eye development, suggesting that this regulatory network was present in a primitive common ancestor and that it has been adapted to control visual organ formation in multiple species. The identification of genes acting upstream and downstream of these transcription factors will contribute to our understanding of the establishment of a developmental field, as well as of the divergence of regulatory pathways controlling the formation of eye structures. Copyright 1999 John Wiley & Sons, Inc.

  33. Zaffran-Maurel, C, Hazelett, DJ, Lee, JD, Benlali, A, Treisman, JE. "The genetic control of early eye development in Drosophila [Abstract]," Developmental biology (Orlando) 1999 JUN 1;210(1):224-224.   (ISI:000080918000267 #J0096093)    

  34. Hazelett DJ, Bourouis M, Walldorf U, Treisman JE. "decapentaplegic and wingless are regulated by eyes absent and eyegone and interact to direct the pattern of retinal differentiation in the eye disc," Development 1998 Sep;125(18):3741-3751.   (MEDL:98384330 PMID: 9716539 #J0002839) Full Text Link!   

    Signaling by the secreted hedgehog, decapentaplegic and wingless proteins organizes the pattern of photoreceptor differentiation within the Drosophila eye imaginal disc; hedgehog and decapentaplegic are required for differentiation to initiate at the posterior margin and progress across the disc, while wingless prevents it from initiating at the lateral margins. Our analysis of these interactions has shown that initiation requires both the presence of decapentaplegic and the absence of wingless, which inhibits photoreceptor differentiation downstream of the reception of the decapentaplegic signal. However, wingless is unable to inhibit differentiation driven by activation of the epidermal growth factor receptor pathway. The effect of wingless is subject to regional variations in control, as the anterior margin of the disc is insensitive to wingless inhibition. The eyes absent and eyegone genes encode members of a group of nuclear proteins required to specify the fate of the eye imaginal disc. We show that both eyes absent and eyegone are required for normal activation of decapentaplegic expression at the posterior and lateral margins of the disc, and repression of wingless expression in presumptive retinal tissue. The requirement for eyegone can be alleviated by inhibition of the wingless signaling pathway, suggesting that eyegone promotes eye development primarily by repressing wingless. These results provide a link between the early specification and later differentiation of the eye disc.

  35. Su YC, Treisman JE, Skolnik EY. "The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway," Genes & development 1998 Aug 1;12(15):2371-2380.   (MEDL:98361879 PMID: 9694801 #J0003201) Full Text Link!   

    Dorsal closure in the Drosophila embryo occurs during the later stages of embryogenesis and involves changes in cell shape leading to the juxtaposition and subsequent adherence of the lateral epidermal primordia over the amnioserosa. Dorsal closure requires the activation of a conserved c-jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) module, as it is blocked by null mutations in JNK kinase [hemipterous (hep)] and JNK [basket (bsk)]. Drosophila JNK (DJNK) functions by phosphorylating and activating DJun, which in turn induces the transcription of decapentaplegic (dpp). We provide biochemical and genetic evidence that a Ste20-related kinase, misshapen (msn), functions upstream of hep and bsk to stimulate dorsal closure in the Drosophila embryo. Mammalian (NCK-interacting kinase [NIK]) and Caenorhabditis elegans (mig-15) homologs of msn have been identified; mig-15 is necessary for several developmental processes in C. elegans. These data suggest that msn, mig-15, and NIK are components of a signaling pathway that is conserved among flies, worms, and mammals to control developmentally regulated pathways.

  36. Treisman JE, Heberlein U. "Eye development in Drosophila: formation of the eye field and control of differentiation," Current topics in developmental biology 1998;39:119-58.   (MEDL:98136476 PMID: 9475999 #J0003226)    

  37. Treisman JE, Luk A, Rubin GM, Heberlein U. "eyelid antagonizes wingless signaling during Drosophila development and has homology to the Bright family of DNA-binding proteins," Genes & development 1997 Aug 1;11(15):1949-1962.   (MEDL:97415319 PMID: 9271118 #J0002298) Full Text Link!   

    In Drosophila, pattern formation at multiple stages of embryonic and imaginal development depends on the same intercellular signaling pathways. We have identified a novel gene, eyelid (eld), which is required for embryonic segmentation, development of the notum and wing margin, and photoreceptor differentiation. In these tissues, eld mutations have effects opposite to those caused by wingless (wg) mutations. eld encodes a widely expressed nuclear protein with a region homologous to a novel family of DNA-binding domains. Based on this homology and on the phenotypic analysis, we suggest that Eld could act as a transcription factor antagonistic to the Wg pathway.

  38. Treisman JE, Ito N, Rubin GM. "misshapen encodes a protein kinase involved in cell shape control in Drosophila," Gene 1997 Feb 20;186(1):119-25.   (MEDL:9047354 PMID: 9047354 #J0079283)    

    We have identified a novel protein kinase encoded by the misshapen gene, which is required for the normal shape and orientation of Drosophila photoreceptor cells. misshapen is also expressed in the embryonic mesoderm, pole plasm and other sites of cell shape change or movement. We propose that msn may act in a signal transduction pathway leading to cytoskeletal re-arrangements.

  39. Chanut, F, Luk, A, Donohoe, T, Treisman, J, Heberlein, U. "Mechanisms of Drosophila retinal morphogenesis: Role of hedgehog and decapentaplegic in furrow progression [Abstract]," Developmental biology (Orlando) 1996 MAY 1;175(2):P16-P16.   (ISI:A1996UK43500033 #J0092822)    

  40. Treisman JE, Rubin GM. "Targets of glass regulation in the Drosophila eye disc," Mechanisms of development 1996 May;56(1-2):17-24.   (MEDL:8798144 PMID: 8798144 #J0079284)    

    The Drosophila glass gene is required for the differentiation and survival of photoreceptors in the compound eye, ocelli and larval photoreceptor organ, glass encodes a zinc finger protein which can activate transcription in cell culture and is likely to act by regulating the expression of other genes. We have shown that it directly or indirectly controls the expression of approximately 25% of all enhancer trap lines expressed in the eye disc. glass gene activity is required to activate 19% of the lines, some of which express beta-galactosidase in photoreceptor subtype-specific patterns, and to repress 6%. The phenotype of eye discs doubly mutant for glass and the homeobox gene rough suggests that glass is required for subtype specification and for recruitment of cells to the ommatidial cluster.

  41. Treisman JE, Follette PJ, O'Farrell PH, Rubin GM. "Cell proliferation and DNA replication defects in a Drosophila MCM2 mutant," Genes & development 1995 Jul 15;9(14):1709-15.   (MEDL:7622035 PMID: 7622035 #J0079287)    

    The yeast MCM2, MCM3, and MCM5/CDC46 genes are required for DNA replication and have been proposed to act as factors that license the DNA for one and only one round of replication per cell cycle. We have identified a Drosophila gene, DmMCM2, that is highly homologous to MCM2. A P-element insertion into this gene, which prevents its transcription, inhibits proliferation of cells in the imaginal discs and central nervous system (CNS) and causes an apparent prolongation of S phase in the embryonic and larval CNS. DmMCM2 is expressed in the embryo in a pattern corresponding to that of S-phase cells. These results suggest that DmMCM2 plays a role in the regulation of DNA replication analogous to that of its yeast counterpart.

  42. Treisman JE, Lai ZC, Rubin GM. "Shortsighted acts in the decapentaplegic pathway in Drosophila eye development and has homology to a mouse TGF-beta-responsive gene," Development 1995 Sep;121(9):2835-45.   (MEDL:7555710 PMID: 7555710 #J0079286)    

    Differentiation in the Drosophila eye imaginal disc traverses the disc as a wave moving from posterior to anterior. The propagation of this wave is driven by hedgehog protein secreted by the differentiated cells in the posterior region of the disc. Hedgehog induces decapentaplegic expression at the front of differentiation, in the morphogenetic furrow. We have identified a gene, shortsighted, which is expressed in a hedgehog-dependent stripe in the undifferentiated cells just anterior to the furrow and which appears to be involved in the transmission of the differentiation-inducing signal; a reduction in shortsighted function leads to a delay in differentiation and to a loss of photoreceptors in the adult. shortsighted is also required for a morphogenetic movement in the brain that reorients the second optic lobe relative to the first. shortsighted encodes a cytoplasmic leucine zipper protein with homology to a mouse gene, TSC-22, which is transcriptionally induced in response to TGF-beta.

  43. Treisman JE, Rubin GM. "wingless inhibits morphogenetic furrow movement in the Drosophila eye disc," Development 1995 Nov;121(11):3519-27.   (MEDL:8582266 PMID: 8582266 #J0079285)    

    Differentiation of the Drosophila eye imaginal disc is an asynchronous, repetitive process which proceeds across the disc from posterior to anterior. Its propagation correlates with the expression of decapentaplegic at the front of differentiation, in the morphogenetic furrow. Both differentiation and decapentaplegic expression are maintained by Hedgehog protein secreted by the differentiated cells posterior to the furrow. However, their initiation at the posterior margin occurs prior to hedgehog expression by an unknown mechanism. We show here that the wingless gene contributes to the correct spatial localization of initiation. Initiation of the morphogenetic furrow is restricted to the posterior margin by the presence of wingless at the lateral margins; removal of wingless allows lateral initiation. Ectopic expression of wingless at the posterior margin can also inhibit normal initiation. In addition, the presence of wingless in the center of the disc can prevent furrow progression. These effects of wingless are achieved without altering the expression of decapentaplegic.

  44. Barnstable CJ, Blum AS, Devoto SH, Hicks D, Morabito MA, Sparrow JR, Treisman JE. "Cell differentiation and pattern formation in the developing mammalian retina," Neuroscience research. Supplement 1988;8:S27-41.   (MEDL:2976483 PMID: 2976483 #J0079289)    

  45. Treisman JE, Morabito MA, Barnstable CJ. "Opsin expression in the rat retina is developmentally regulated by transcriptional activation," Molecular & cellular biology 1988 Apr;8(4):1570-9.   (MEDL:2967911 PMID: 2967911 #J0079288)    

    The gene for rhodopsin, the primary light sensor of the visual system, is specifically expressed in the rod photoreceptor cells of the retina. We show here that in the rat, opsin RNA first accumulates to detectable levels at postnatal day 2 (PN2) and that nascent transcripts can be detected at PN1; this is the time when peak numbers of photoreceptor cells are generated by the final division of their neuroepithelial precursors. Accumulated opsin RNA then increases to reach the adult level, 0.06% of total retinal RNA, at about PN10. The transcription rate of the opsin gene increases to a similar extent over the same time course between PN3 and adulthood, suggesting that transcriptional activation is responsible for the increase in opsin expression. We used the antibody RET-P1 to show that rhodopsin protein is also detectable at PN2 and that the number of cells expressing the protein increases with time in a central-to-peripheral gradient in the retina. This increase in the number of differentiating photoreceptors in the tissue appears to account for much of the increase in opsin gene transcription and RNA accumulation. In situ hybridization to opsin RNA shows that it is restricted to the photoreceptor layer from the time it can first be detected, at PN7. Later in development, when RET-P1 staining shifts to the photoreceptor outer segments, opsin RNA becomes localized to the inner segments, suggesting that the distributions of opsin protein and RNA are related.





Ehrman Medical Library Faculty Bibliography Search printed 05/13/2008 18:24


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