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Leptin GroupPublications

Molecular mechanisms of de novo lumen formation.
Sigurbjornsdottir, S., Mathew, R. & Leptin, M.
Nat Rev Mol Cell Biol. 2014 Sep 4. doi: 10.1038/nrm3871.
Many organs contain networks of epithelial tubes that transport gases or fluids. A lumen can be generated by tissue that enwraps a pre-existing extracellular space or it can arise de novo either between cells or within a single cell in a position where there was no space previously. Apparently distinct mechanisms of de novo lumen formation observed in vitro - in three-dimensional cultures of endothelial and Madin-Darby canine kidney (MDCK) cells - and in vivo - in zebrafish vasculature, Caenorhabditis elegans excretory cells and the Drosophila melanogaster trachea - in fact share many common features. In all systems, lumen formation involves the structured expansion of the apical plasma membrane through general mechanisms of vesicle transport and of microtubule and actin cytoskeleton regulation.
Europe PMC

Systemic response to ultraviolet radiation involves induction of leukocytic IL-1beta and inflammation in zebrafish.
Banerjee, S. & Leptin, M.
J Immunol. 2014 Aug 1;193(3):1408-15. doi: 10.4049/jimmunol.1400232. Epub 2014Jun 25.
Ultraviolet radiation is a pervasive stimulus with wide-ranging effects on all living forms. The effects of UV vary from physiological to pathological, depending on levels of exposure, but the immune response at the organismal level is not well understood. We use the zebrafish embryo and larva to study immune responses to UV stress in vivo. UV exposure causes inflammation characterized by systemic induction of proinflammatory cytokines. Leukocytes are an important component of this systemic response and upregulate IL-1beta expression proportional to the dose of UV exposure. Increased levels of this proinflammatory cytokine counteract the lethal effect of high doses of UV.
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Slik and the Receptor Tyrosine Kinase Breathless Mediate Localized Activation of Moesin in Terminal Tracheal Cells.
Ukken, F.P., Aprill, I., JayaNandanan, N. & Leptin, M.
PLoS One. 2014 Jul 25;9(7):e103323. doi: 10.1371/journal.pone.0103323.eCollection 2014.
A key element in the regulation of subcellular branching and tube morphogenesis of the Drosophila tracheal system is the organization of the actin cytoskeleton by the ERM protein Moesin. Activation of Moesin within specific subdomains of cells, critical for its interaction with actin, is a tightly controlled process and involves regulatory inputs from membrane proteins, kinases and phosphatases. The kinases that activate Moesin in tracheal cells are not known. Here we show that the Sterile-20 like kinase Slik, enriched at the luminal membrane, is necessary for the activation of Moesin at the luminal membrane and regulates branching and subcellular tube morphogenesis of terminal cells. Our results reveal the FGF-receptor Breathless as an additional necessary cue for the activation of Moesin in terminal cells. Breathless-mediated activation of Moesin is independent of the canonical MAP kinase pathway.
Europe PMC

Guidance of subcellular tubulogenesis by actin under the control of a synaptotagmin-like protein and Moesin.
Jayanandanan, N., Mathew, R. & Leptin, M.
Nat Commun. 2014 Jan 13;5:3036. doi: 10.1038/ncomms4036.
Apical membranes in many polarized epithelial cells show specialized morphological adaptations that fulfil distinct physiological functions. The air-transporting tubules of Drosophila tracheal terminal cells represent an extreme case of membrane specialization. Here we show that Bitesize (Btsz), a synaptotagmin-like protein family member, is needed for luminal membrane morphogenesis. Unlike in multicellular tubes and other epithelia, where it influences apical integrity by affecting adherens junctions, Btsz here acts at a distance from junctions. Localized at the luminal membrane through its tandem C2 domain, it recruits activated Moesin. Both proteins are needed for the integrity of the actin cytoskeleton at the luminal membrane, but not for other pools of F-actin in the cell, nor do actin-dependent processes at the outer membrane, such as filopodial activity or membrane growth depend on Btsz. Btsz and Moesin guide luminal membrane morphogenesis through organizing actin and allowing the incorporation of membrane containing the apical determinant Crumbs.
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Physical models of mesoderm invagination in Drosophila embryo.
Rauzi, M., Hocevar Brezavscek, A., Ziherl, P. & Leptin, M.
Biophys J. 2013 Jul 2;105(1):3-10. doi: 10.1016/j.bpj.2013.05.039.
The invagination of the mesoderm in the Drosophila melanogaster embryo is an intensely studied example of epithelial folding. Several theoretical studies have explored the conditions and mechanisms needed to reproduce the formation of the invagination in silico. Here we discuss the aspects of epithelial folding captured by these studies, and compare the questions addressed, the approaches used, and the answers provided.
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Microsomal triacylglycerol transfer protein (MTP) is required to expand tracheal lumen in Drosophila in a cell-autonomous manner.
Baer, M.M., Palm, W., Eaton, S., Leptin, M. & Affolter, M.
J Cell Sci. 2012 Dec 15;125(Pt 24):6038-48. doi: 10.1242/jcs.110452. Epub 2012Nov 6.
The Drosophila tracheal system is a useful model for dissecting the molecular mechanisms controlling the assembly and expansion of tubular organs. We have identified microsomal triacylglycerol transfer protein (MTP) as a new player involved in the lumen expansion in unicellular tubes. MTP is an endoplasmic reticulum resident protein that can transfer triglycerides and phospholipids between membranes in vitro. MTP lipid transfer activity is crucial for the assembly and secretion of apoB family lipoproteins, which are carriers of lipids between different tissues. Here we describe an unexpected role of MTP in tracheal development, which we postulate to be independent of its known function in lipoprotein secretion. We propose that, in tracheal cells, MTP is involved in regulation of de novo apical membrane delivery to the existing lumen and thus promotes proper expansion of the larval tracheal system.
Europe PMC

A model of epithelial invagination driven by collective mechanics of identical cells.
Hocevar Brezavscek, A., Rauzi, M., Leptin, M. & Ziherl, P.
Biophys J. 2012 Sep 5;103(5):1069-77.
We propose a 2D mechanical model of a tubular epithelium resembling the early Drosophila embryo. The model consists of a single layer of identical cells with energy associated with the tension of cell cortex. Depending on the relative tension of the apical, basal, and lateral sides of the cells, tissue thickness, and the degree of external constraint, the minimal-energy states of the epithelial cross section include circular shapes as well as a range of inward-buckled shapes. Some of the solutions are characterized by a single deep groove, which shows that an epithelium consisting of cells of identical mechanical properties can infold. This is consistent with what is seen in embryos of certain Drosophila mutants. To ensure that the infolding occurs at a predetermined section of the epithelium, we extend the model by increasing the cross-sectional area of a subset of cells, which is consistent with observations in wild-type embryos. This variation of cell parameters across the epithelium is sufficient to make it fold at a specific site. The model explores previously untested minimal conditions for tissue invagination and is devoid of specificity needed to accurately describe an in vivo situation in Drosophila.
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Open access--pass the buck.
Leptin, M.
Science. 2012 Mar 16;335(6074):1279. doi: 10.1126/science.1220395. Europe PMC

A role for Traf4 in polarizing adherens junctions as a prerequisite for efficient cell shape changes.
Mathew, S.J., Rembold, M. & Leptin, M.
Mol Cell Biol. 2011 Dec;31(24):4978-93. doi: 10.1128/MCB.05542-11. Epub 2011 Oct10.
Apical constriction of epithelial cells is a widely used morphogenetic mechanism. In the Drosophila embryo, the apical constrictions that internalize the mesoderm are controlled by the transcription factor Twist and require intact adherens junctions and a contractile acto-myosin network. We find that adherens junctions in constricting mesodermal cells undergo extensive remodeling. A Twist target gene encoding a member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family, Traf4, is involved in this process. While TRAFs are best known for their functions in inflammatory responses, Traf4 appears to have a different role, and its mechanism of action is poorly understood. We show that Traf4 is required for efficient apical constriction during ventral furrow formation and for proper localization of Armadillo to the apical position in constricting cells. Traf4 and Armadillo interact with each other physically and functionally. Traf4 acts in a TNF receptor- and Jun N-terminal protein kinase (JNK)-independent manner to fine-tune the assembly of adherens junctions in the invaginating mesodermal cells.
Europe PMC

A genetic in vivo system to detect asymmetrically distributed RNA.
JayaNandanan, N., Gavis, E.R., Riechmann, V. & Leptin, M.
EMBO Rep. 2011 Oct 28;12(11):1167-74. doi: 10.1038/embor.2011.178.
Many RNAs show polarized or otherwise non-random subcellular distributions. To create a method for genome-wide genetic screens for RNAs with asymmetric subcellular distributions, we have combined methods for gene tagging and live imaging of messenger RNA (mRNA). A pilot screen in a highly polarized, differentiated cell in the Drosophila larva, the branched terminal cell of the tracheal system, demonstrates the feasibility of the method for identifying new asymmetrically localized mRNAs in vivo.
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Fibroblast growth factor signalling controls successive cell behaviours during mesoderm layer formation in Drosophila.
Clark, I.B., Muha, V., Klingseisen, A., Leptin, M. & Muller, H.A.
Development. 2011 Jul;138(13):2705-15. Epub 2011 May 25.
Fibroblast growth factor (FGF)-dependent epithelial-mesenchymal transitions and cell migration contribute to the establishment of germ layers in vertebrates and other animals, but a comprehensive demonstration of the cellular activities that FGF controls to mediate these events has not been provided for any system. The establishment of the Drosophila mesoderm layer from an epithelial primordium involves a transition to a mesenchymal state and the dispersal of cells away from the site of internalisation in a FGF-dependent fashion. We show here that FGF plays multiple roles at successive stages of mesoderm morphogenesis in Drosophila. It is first required for the mesoderm primordium to lose its epithelial polarity. An intimate, FGF-dependent contact is established and maintained between the germ layers through mesoderm cell protrusions. These protrusions extend deep into the underlying ectoderm epithelium and are associated with high levels of E-cadherin at the germ layer interface. Finally, FGF directs distinct hitherto unrecognised and partially redundant protrusive behaviours during later mesoderm spreading. Cells first move radially towards the ectoderm, and then switch to a dorsally directed movement across its surface. We show that both movements are important for layer formation and present evidence suggesting that they are controlled by genetically distinct mechanisms.
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In Vivo Analysis of Ifn-{gamma}1 and Ifn-{gamma}2 Signaling in Zebrafish.
Aggad, D., Stein, C., Sieger, D., Mazel, M., Boudinot, P., Herbomel, P., Levraud, J.P., Lutfalla, G. & Leptin, M.
J Immunol. 2010 Dec 1;185(11):6774-82. Epub 2010 Nov 3.
The zebrafish genome contains a large number of genes encoding potential cytokine receptor genes as judged by homology to mammalian receptors. The sequences are too divergent to allow unambiguous assignments of all receptors to specific cytokines, and only a few have been assigned functions by functional studies. Among receptors for class II helical cytokines-i.e., IFNs that include virus-induced Ifns (Ifn-) and type II Ifns (Ifn-gamma), together with Il-10 and its related cytokines (Il-20, Il-22, and Il-26)-only the Ifn--specific complexes have been functionally identified, whereas the receptors for the two Ifn-gamma (Ifn-gamma1 and Ifn-gamma2) are unknown. In this work, we identify conditions in which Ifn-gamma1 and Ifn-gamma2 (also called IFNG or IFN-gamma and IFN-gammarel) are induced in fish larvae and adults. We use morpholino-mediated loss-of-function analysis to screen candidate receptors and identify the components of their receptor complexes. We find that Ifn-gamma1 and Ifn-gamma2 bind to different receptor complexes. The receptor complex for Ifn-gamma2 includes cytokine receptor family B (Crfb)6 together with Crfb13 and Crfb17, whereas the receptor complex for Ifn-gamma1 does not include Crfb6 or Crfb13 but includes Crfb17. We also show that of the two Jak2 paralogues present in the zebrafish Jak2a but not Jak2b is involved in the intracellular transmission of the Ifn-gamma signal. These results shed new light on the evolution of the Ifn-gamma signaling in fish and tetrapods and contribute toward an integrated view of the innate immune regulation in vertebrates.
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A novel conserved phosphotyrosine motif in the Drosophila fibroblast growth factor signaling adaptor Dof with a redundant role in signal transmission.
Csiszar, A., Vogelsang, E., Beug, H. & Leptin, M.
Mol Cell Biol. 2010 Apr;30(8):2017-27. Epub 2010 Feb 12.
The fibroblast growth factor receptor (FGFR) signals through adaptors constitutively associated with the receptor. In Drosophila melanogaster, the FGFR-specific adaptor protein Downstream-of-FGFR (Dof) becomes phosphorylated upon receptor activation at several tyrosine residues, one of which recruits Corkscrew (Csw), the Drosophila homolog of SHP2, which provides a molecular link to mitogen-activated protein kinase (MAPK) activation. However, the Csw pathway is not the only link from Dof to MAPK. In this study, we identify a novel phosphotyrosine motif present in four copies in Dof and also found in other insect and vertebrate signaling molecules. We show that these motifs are phosphorylated and contribute to FGF signal transduction. They constitute one of three sets of phosphotyrosines that act redundantly in signal transmission: (i) a Csw binding site, (ii) four consensus Grb2 recognition sites, and (iii) four novel tyrosine motifs. We show that Src64B binds to Dof and that Src kinases contribute to FGFR-dependent MAPK activation. Phosphorylation of the novel tyrosine motifs is required for the interaction of Dof with Src64B. Thus, Src64B recruitment to Dof through the novel phosphosites can provide a new link to MAPK activation and other cellular responses. This may give a molecular explanation for the involvement of Src kinases in FGF-dependent developmental events.
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The role of apoptosis in shaping the tracheal system in the Drosophila embryo.
Baer, M.M., Bilstein, A., Caussinus, E., Csiszar, A., Affolter, M. & Leptin, M.
Mech Dev. 2010 Jan-Feb;127(1-2):28-35. Epub 2009 Dec 6.
The tubular network of the tracheal system in the Drosophila embryo is created from a set of epithelial placodes by cell migration, rearrangements, fusions and shape changes. A designated number of cells is initially allocated to each branch of the system. We show here that the final cell number in the dorsal branches is not only determined by early patterning events and subsequent cell rearrangements but also by elimination of cells from the developing branch. Extruded cells die and are engulfed by macrophages. Our results suggest that the pattern of cell extrusion and death is not hard-wired, but is determined by environmental cues.
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The role of gamma interferon in innate immunity in the zebrafish embryo.
Sieger, D., Stein, C., Neifer, D., van der Sar, A.M. & Leptin, M.
Dis Model Mech. 2009 Nov-Dec;2(11-12):571-81. doi: 10.1242/dmm.003509. Epub 2009Sep 24.
The zebrafish genome contains ten genes that encode class II cytokine-like peptides, of which the two that are related most closely to mammalian interferon gamma (IFN-gamma) were named IFN-gamma1 and IFN-gamma2. Although the zebrafish has become a popular model system to study immune mechanisms, and although interferons are central regulators of immunity, which zebrafish cytokines correspond functionally to mammalian IFN-gamma has not been established. We used zebrafish embryos to assay the functions of IFN-gamma1 and IFN-gamma2, and have identified a subset of zebrafish homologs of the mammalian IFN-responsive genes as IFN-gamma targets in the zebrafish embryo: these genes are upregulated in response to raised levels of either IFN-gamma1 or IFN-gamma2. Infection studies using two different pathogens show that IFN-gamma signalling is required for resistance against bacterial infections in the young embryo and that the levels of IFN-gamma need to be regulated tightly: raising IFN-gamma levels sensitizes fish embryos against bacterial infection. Embryos injected with high doses of Escherichia coli are able to clear the bacteria within a day, and the gamma-interferons are necessary for this defence reaction. The protective response to Yersinia ruckeri, a natural fish pathogen that is lethal at low doses, also requires IFN-gamma. As in the induction of target genes, the two interferons act at least partly redundantly. Together with the previously demonstrated type III interferon response, these results show that the counterparts of the mammalian viral and bacterial interferon-dependent defence functions are in place in zebrafish embryos, and suggest that zebrafish IFN-gamma1 and IFN-gamma2 are functionally equivalent to mammalian IFN-gamma.
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Looking beyond death: a morphogenetic role for the TNF signalling pathway.
Mathew, S.J., Haubert, D., Kronke, M. & Leptin, M.
J Cell Sci. 2009 Jun 15;122(Pt 12):1939-46.
Tumour necrosis factor alpha (TNFalpha) is a pro-inflammatory mediator with the capacity to induce apoptosis. An integral part of its apoptotic and inflammatory programmes is the control of cell shape through modulation of the cytoskeleton, but it is now becoming apparent that this morphogenetic function of TNF signalling is also employed outside inflammatory responses and is shared by the signalling pathways of other members of the TNF-receptor superfamily. Some proteins that are homologous to the components of the TNF signalling pathway, such as the adaptor TNF-receptor-associated factor 4 and the ectodysplasin A receptor (and its ligand and adaptors), have dedicated morphogenetic roles. The mechanism by which TNF signalling affects cell shape is not yet fully understood, but Rho-family GTPases have a central role. The fact that the components of the TNF signalling pathway are evolutionarily old suggests that an ancestral cassette from unicellular organisms has diversified its functions into partly overlapping morphogenetic, inflammatory and apoptotic roles in multicellular higher organisms.
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A small genomic region containing several loci required for gastrulation in Drosophila.
Mathew, S.J., Kerridge, S. & Leptin, M.
PLoS One. 2009 Oct 13;4(10):e7437.
Genetic screens in Drosophila designed to search for loci involved in gastrulation have identified four regions of the genome that are required zygotically for the formation of the ventral furrow. For three of these, the genes responsible for the mutant phenotypes have been found. We now describe a genetic characterization of the fourth region, which encompasses the cytogenetic interval 24C3-25B, and the mapping of genes involved in gastrulation in this region. We have determined the precise breakpoints of several existing deficiencies and have generated new deficiencies. Our results show that the region contains at least three different loci associated with gastrulation effects. One maternal effect gene involved in ventral furrow formation maps at 24F but could not be identified. For a second maternal effect gene which is required for germ band extension, we identify a candidate gene, CG31660, which encodes a G protein coupled receptor. Finally, one gene acts zygotically in ventral furrow formation and we identify it as Traf4.
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A genetic mosaic analysis with a repressible cell marker screen to identify genes involved in tracheal cell migration during Drosophila air sac morphogenesis.
Chanut-Delalande, H., Jung, A.C., Lin, L., Baer, M.M., Bilstein, A., Cabernard, C., Leptin, M. & Affolter, M.
Genetics. 2007 Aug;176(4):2177-87. Epub 2007 Jul 1.
Branching morphogenesis of the Drosophila tracheal system relies on the fibroblast growth factor receptor (FGFR) signaling pathway. The Drosophila FGF ligand Branchless (Bnl) and the FGFR Breathless (Btl/FGFR) are required for cell migration during the establishment of the interconnected network of tracheal tubes. However, due to an important maternal contribution of members of the FGFR pathway in the oocyte, a thorough genetic dissection of the role of components of the FGFR signaling cascade in tracheal cell migration is impossible in the embryo. To bypass this shortcoming, we studied tracheal cell migration in the dorsal air sac primordium, a structure that forms during late larval development. Using a mosaic analysis with a repressible cell marker (MARCM) clone approach in mosaic animals, combined with an ethyl methanesulfonate (EMS)-mutagenesis screen of the left arm of the second chromosome, we identified novel genes implicated in cell migration. We screened 1123 mutagenized lines and identified 47 lines displaying tracheal cell migration defects in the air sac primordium. Using complementation analyses based on lethality, mutations in 20 of these lines were genetically mapped to specific genomic areas. Three of the mutants were mapped to either the Mhc or the stam complementation groups. Further experiments confirmed that these genes are required for cell migration in the tracheal air sac primordium.
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A clonal genetic screen for mutants causing defects in larval tracheal morphogenesis in Drosophila.
Baer, M.M., Bilstein, A. & Leptin, M.
Genetics. 2007 Aug;176(4):2279-91. Epub 2007 Jul 1.
The initial establishment of the tracheal network in the Drosophila embryo is beginning to be understood in great detail, both in its genetic control cascades and in its cell biological events. By contrast, the vast expansion of the system during larval growth, with its extensive ramification of preexisting tracheal branches, has been analyzed less well. The mutant phenotypes of many genes involved in this process are probably not easy to reveal, as these genes may be required for other functions at earlier developmental stages. We therefore conducted a screen for defects in individual clonal homozygous mutant cells in the tracheal network of heterozygous larvae using the mosaic analysis with a repressible cell marker (MARCM) system to generate marked, recombinant mitotic clones. We describe the identification of a set of mutants with distinct phenotypic effects. In particular we found a range of defects in terminal cells, including failure in lumen formation and reduced or extensive branching. Other mutations affect cell growth, cell shape, and cell migration.
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Analysis and reconstitution of the genetic cascade controlling early mesoderm morphogenesis in the Drosophila embryo.
Seher, T.C., Narasimha, M., Vogelsang, E. & Leptin, M.
Mech Dev. 2007 Mar;124(3):167-79. Epub 2006 Dec 27.
To understand how transcription factors direct developmental events, it is necessary to know their target or 'effector' genes whose products mediate the downstream cell biological events. Whereas loss of a single target may partially or fully recapitulate the phenotype of loss of the transcription factor, this does not mean that this target is the only direct mediator. For a complete understanding of the pathway it is necessary to identify the full set of targets that together are sufficient to carry out the programme initiated by the transcription factor, which has not yet been attempted for any pathway. In the case of the transcriptional activator Twist, which acts at the top of the mesodermal developmental cascade in Drosophila, two targets, Snail and Fog, are known to be necessary for the first morphogenetic event, the orderly invagination of the mesoderm. We use a system of reconstituting loss of Twist function by transgenes expressing Snail and Fog independently of Twist to analyse the sufficiency of these factors-a loss of function assay for additional gene functions to assess what further functions might be needed downstream of Twist. Confirming and extending previous studies, we show that Snail plays an essential role, allowing basic cell shape changes to take place. Fog and at least two other genes are needed to accelerate and coordinate shape changes. Furthermore, this study represents the first step in the systematic reconstruction of the morphogenetic programme downstream of Twist.
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Control of Drosophila gastrulation by apical localization of adherens junctions and RhoGEF2.
Kolsch, V., Seher, T., Fernandez-Ballester, G.J., Serrano, L. & Leptin, M.
Science. 2007 Jan 19;315(5810):384-6.
A hallmark of epithelial invagination is the constriction of cells on their apical sides. During Drosophila gastrulation, apical constrictions under the control of the transcription factor Twist lead to the invagination of the mesoderm. Twist-controlled G protein signaling is involved in mediating the invagination but is not sufficient to account for the full activity of Twist. We identified a Twist target, the transmembrane protein T48, which acts in conjunction with G protein signaling to orchestrate shape changes. Together with G protein signaling, T48 recruits adherens junctions and the cytoskeletal regulator RhoGEF2 to the sites of apical constriction, ensuring rapid and intense changes in cell shape.
Europe PMC

Conservation and divergence of gene families encoding components of innate immune response systems in zebrafish.
Stein, C., Caccamo, M., Laird, G. & Leptin, M.
Genome Biol. 2007;8(11):R251.
BACKGROUND: The zebrafish has become a widely used model to study disease resistance and immunity. Although the genes encoding many components of immune signaling pathways have been found in teleost fish, it is not clear whether all components are present or whether the complexity of the signaling mechanisms employed by mammals is similar in fish. RESULTS: We searched the genomes of the zebrafish Danio rerio and two pufferfish for genes encoding components of the Toll-like receptor and interferon signaling pathways, the NLR (NACHT-domain and leucine rich repeat containing) protein family, and related proteins. We find that most of the components known in mammals are also present in fish, with clearly recognizable orthologous relationships. The class II cytokines and their receptors have diverged extensively, obscuring orthologies, but the number of receptors is similar in all species analyzed. In the family of the NLR proteins, the canonical members are conserved. We also found a conserved NACHT-domain protein with WD40 repeats that had previously not been described in mammals. Additionally, we have identified in each of the three fish a large species-specific subgroup of NLR proteins that contain a novel amino-terminal domain that is not found in mammalian genomes. CONCLUSION: The main innate immune signaling pathways are conserved in mammals and teleost fish. Whereas the components that act downstream of the receptors are highly conserved, with orthologous sets of genes in mammals and teleosts, components that are known or assumed to interact with pathogens are more divergent and have undergone lineage-specific expansions.
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A screen for genes that influence fibroblast growth factor signal transduction in Drosophila.
Zhu, M.Y., Wilson, R. & Leptin, M.
Genetics. 2005 Jun;170(2):767-77. Epub 2005 Apr 16.
The misexpression of an activated form of the FGF receptor (FGFR) Breathless in conjunction with downstream-of-FGF-receptor (Dof), an essential signaling molecule of the FGF pathway, in the Drosophila eye imaginal discs impairs eye development and results in a rough eye phenotype. We used this phenotype in a gain-of-function screen to search for modifiers of FGF signaling. We identified 50 EP stocks with insertions defining at least 35 genes that affect the rough eye phenotype. Among these genes, 4 appear to be specific for FGFR signaling, but most of the genes also influence other signaling pathways, as assessed by their effects on rough eyes induced by other activated receptor tyrosine kinases (RTKs). Analysis of loss-of-function alleles of a number of these genes in embryos indicates that in many cases the products are provided maternally and are involved in germ cell development. At least two of the genes, sar1 and robo2, show a genetic interaction with a hypomorphic dof allele, suggesting that they participate in FGF-mediated morphogenetic events during embryogenesis.
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Gastrulation movements: the logic and the nuts and bolts.
Leptin, M.
Dev Cell. 2005 Mar;8(3):305-20.
Gastrulation, the period during the early development of animals when major cell and tissue movements remodel an initially unstructured group of cells, requires coordinated control of different types of cellular activities in different cell populations. A hierarchy of genetic control mechanisms, involving cell signaling and transcriptional regulation, sets up the embryonic axes and specify the territories of the future germ layers. Cells in these territories modulate their cytoskeleton and their adhesive behavior, resulting in shape changes and movement. Similarities among different species in patterning and cell biological mechanisms are beginning to allow us to recognize general, conserved principles and speculate on possible ancestral mechanisms of gastrulation.
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The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage.
Bekpen, C., Hunn, J.P., Rohde, C., Parvanova, I., Guethlein, L., Dunn, D.M., Glowalla, E., Leptin, M. & Howard, J.C.
Genome Biol. 2005;6(11):R92. Epub 2005 Oct 31.
BACKGROUND: Members of the p47 (immunity-related GTPases (IRG) family) GTPases are essential, interferon-inducible resistance factors in mice that are active against a broad spectrum of important intracellular pathogens. Surprisingly, there are no reports of p47 function in humans. RESULTS: Here we show that the p47 GTPases are represented by 23 genes in the mouse, whereas humans have only a single full-length p47 GTPase and an expressed, truncated presumed pseudo-gene. The human full-length gene is orthologous to an isolated mouse p47 GTPase that carries no interferon-inducible elements in the promoter of either species and is expressed constitutively in the mature testis of both species. Thus, there is no evidence for a p47 GTPase-based resistance system in humans. Dogs have several interferon-inducible p47s, and so the primate lineage that led to humans appears to have lost an ancient function. Multiple p47 GTPases are also present in the zebrafish, but there is only a tandem p47 gene pair in pufferfish. CONCLUSION: Mice and humans must deploy their immune resources against vacuolar pathogens in radically different ways. This carries significant implications for the use of the mouse as a model of human infectious disease. The absence of the p47 resistance system in humans suggests that possession of this resistance system carries significant costs that, in the primate lineage that led to humans, are not outweighed by the benefits. The origin of the vertebrate p47 system is obscure.
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