Notch Signalling and Ciliogenesis

Objectives

We concentrate on two topics: analyses of Notch signal transduction and functional characterization of ciliary proteins.

The evolutionary conserved Notch signaling pathway mediates cell-to-cell communication between adjacent cells and regulates differentiation and proliferation depending on the cellular context. Mutations in Notch pathway components disrupt specific aspects of embryonic development in diverse organisms and are causative for human diseases. Here we want to better understand the function of ligands.

Cilia are microtubule-based cellular projections that have essential signaling or motility functions. Consistent with essential ciliary functions defects in cilia disrupt normal development and tissue homeostasis, and underlie various human diseases that are collectively referred to as ciliopathies. Here, we concentrate on the analysis of uncharacterized components of motile cilia.

Research Focus

Notch signaling: we analyze various aspects of Notch ligand biochemistry and function concentrating on the highly similar mammalian Notch ligands DLL1 and DLL4. We focus on the analysis of the functional (non)equivalence of these Notch Delta ligands during development and their context-dependent activity, using the mouse as the animal model of choice and employing a combination of biochemical, molecular genetic, and transgenic methods

Ciliogenesis: we have identified a number of proteins with unknown biochemical functions that are expressed in cells carrying motile cilia. We have generated several new mouse models for primary cilia dyskinesia (PCD). PCD is a specific group of ciliopathies that is characterized by combinations of respiratory problems, infertility, and situs defects in affected individuals. Ongoing projects characterize these mouse models and the biochemical function of selected proteins.

Collaborations

  • M.Sc. Biomedicine, B.Sc. Biology. Ph.D. programme

Awards

  • A. Beckers, ‘Doktorandenpreis MHH’ (2008)

Publications

2013 - ongoing

2017

Schmitz F, Burtscher I, Stauber M, Gossler A, Lickert H. A novel Cre-inducible knock-in ARL13B-tRFP fusion cilium reporter. genesis. 2017;55(11):e23073-n/a.

Stauber M, Boldt K, Wrede C, Weidemann M, Kellner M, Schuster-Gossler K, Kühnel MP, Hegermann J, Ueffing M, Gossler A. 1700012B09Rik, a FOXJ1 effector gene active in ciliated tissues of the mouse but not essential for motile ciliogenesis. Developmental Biology. 2017;429(1):186-99.

Stauber M, Weidemann M, Dittrich-Breiholz O, Lobschat K, Alten L, Mai M, Beckers A, Kracht M, Gossler A. Identification of FOXJ1 effectors during ciliogenesis in the foetal respiratory epithelium and embryonic left-right organiser of the mouse. Developmental Biology. 2017;423(2):170-88.

2016

Weidemann M, Schuster-Gossler K, Stauber M, Wrede C, Hegermann J, Ott T, Boldt K, Beyer T, Serth K, Kremmer E, Blum M, Ueffing M, Gossler A. CFAP157 is a murine downstream effector of FOXJ1 that is specifically required for flagellum morphogenesis and sperm motility. Development. 2016;143(24):4736-48.

Stauber M, Weidemann M, Dittrich-Breiholz O, Lobschat K, Alten L, Mai M, Beckers A, Kracht M, Gossler A. Identification of FOXJ1 effectors during ciliogenesis in the foetal respiratory epithelium and embryonic left-right organiser of the mouse. Developmental biology. 2016.

Schuster-Gossler K, Cordes R, Muller J, Geffers I, Delany-Heiken P, Taft M, Preller M, Gossler A. Context-Dependent Sensitivity to Mutations Disrupting the Structural Integrity of Individual EGF Repeats in the Mouse Notch Ligand DLL1. Genetics. 2016;202(3):1119-33.

2015

Serth K, Schuster-Gossler K, Kremmer E, Hansen B, Marohn-Kohn B, Gossler A. O-Fucosylation of Dll3 Is Required for Its Function During Somitogenesis. PLoS One. 2015;10(4):e0123776. Epub 2015/04/10.

Preusse K, Tveriakhina L, Schuster-Gossler K, Gaspar C, Rosa AI, Henrique D, Gossler A, Stauber M. Context-Dependent Functional Divergence of the Notch Ligands Dll1 and Dll4 in Vivo. PLoS Genet. 2015;11(6):e1005328.

2014

Muller J, Rana NA, Serth K, Kakuda S, Haltiwanger RS, Gossler A. O-Fucosylation of the Notch Ligand Mdll1 by Pofut1 Is Dispensable for Ligand Function. PLoS One. 2014;9(2):e88571. Epub 2014/02/18.

Menon MB, Sawada A, Chaturvedi A, Mishra P, Schuster-Gossler K, Galla M, Schambach A, Gossler A, Forster R, Heuser M, Kotlyarov A, Kinoshita M, Gaestel M. Genetic Deletion of Sept7 Reveals a Cell Type-Specific Role of Septins in Microtubule Destabilization for the Completion of Cytokinesis. PLoS Genet. 2014;10(8):e1004558.

Braune EB, Schuster-Gossler K, Lyszkiewicz M, Serth K, Preusse K, Madlung J, Macek B, Krueger A, Gossler A. S/T Phosphorylation of Dll1 Is Required for Full Ligand Activity in Vitro but Dispensable for Dll1 Function in Vivo During Embryonic Patterning and Marginal Zone B Cell Development. Mol Cell Biol. 2014;34(7):1221-33. Epub 2014/01/23.

2013

Zender S, Nickeleit I, Wuestefeld T, Sorensen I, Dauch D, Bozko P, El-Khatib M, Geffers R, Bektas H, Manns MP, Gossler A, Wilkens L, Plentz R, Zender L, Malek NP. A Critical Role for Notch Signaling in the Formation of Cholangiocellular Carcinomas. Cancer Cell. 2013;23(6):784-95.

Redeker C, Schuster-Gossler K, Kremmer E, Gossler A. Normal Development in Mice over-Expressing the Intracellular Domain of Dll1 Argues against Reverse Signaling by Dll1 in Vivo. PLoS One. 2013;8(10):e79050.

2006 - 2012

2012

Alten L, Schuster-Gossler K, Eichenlaub MP, Wittbrodt B, Wittbrodt J, Gossler A. A Novel Mammal-Specific Three Partite Enhancer Element Regulates Node and Notochord-Specific Noto Expression. PLoS One. 2012;7(10):e47785.

Alten L, Schuster-Gossler K, Beckers A, Groos S, Ulmer B, Hegermann J, Ochs M, Gossler A. Differential Regulation of Node Formation, Nodal Ciliogenesis and Cilia Positioning by Noto and Foxj1. Development. 2012;139(7):1276-84.

2011

Hoch M, Fischer P, Stapel B, Missol-Kolka E, Sekkali B, Scherr M, Favret F, Braun T, Eder M, Schuster-Gossler K, Gossler A, Hilfiker A, Balligand JL, Drexler H, Hilfiker-Kleiner D. Erythropoietin Preserves the Endothelial Differentiation Capacity of Cardiac Progenitor Cells and Reduces Heart Failure During Anticancer Therapies. Cell Stem Cell. 2011;9(2):131-43.

Girós A, Grgur K, Gossler A, Costell M. Α5β1 Integrin-Mediated Adhesion to Fibronectin Is Required for Axis Elongation and Somitogenesis in Mice. PLoS ONE. 2011;6(7):e22002.

2009

Sorensen I, Adams RH, Gossler A. Dll1-Mediated Notch Activation Regulates Endothelial Identity in Mouse Fetal Arteries. Blood. 2009;113(22):5680-8.

Schuster-Gossler K, Harris B, Johnson KR, Serth J, Gossler A. Notch Signalling in the Paraxial Mesoderm Is Most Sensitive to Reduced Pofut1 Levels During Early Mouse Development. BMC Dev Biol. 2009;9:6. Epub 2009/01/24.

Rocha SF, Lopes SS, Gossler A, Henrique D. Dll1 and Dll4 Function Sequentially in the Retina and Pv2 Domain of the Spinal Cord to Regulate Neurogenesis and Create Cell Diversity. Dev Biol. 2009;328(1):54-65.

Feyerabend TB, Terszowski G, Tietz A, Blum C, Luche H, Gossler A, Gale NW, Radtke F, Fehling HJ, Rodewald HR. Deletion of Notch1 Converts Pro-T Cells to Dendritic Cells and Promotes Thymic B Cells by Cell-Extrinsic and Cell-Intrinsic Mechanisms. Immunity. 2009;30(1):67-79.

Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, Adams RH. The Notch Ligands Dll4 and Jagged1 Have Opposing Effects on Angiogenesis. Cell. 2009;137(6):1124-35. Epub 2009/06/16.

2008

Feller J, Schneider A, Schuster-Gossler K, Gossler A. Noncyclic Notch Activity in the Presomitic Mesoderm Demonstrates Uncoupling of Somite Compartmentalization and Boundary Formation. Genes Dev. 2008;22(16):2166-71.

Estrach S, Cordes R, Hozumi K, Gossler A, Watt FM. Role of the Notch Ligand Delta1 in Embryonic and Adult Mouse Epidermis. J Invest Dermatol. 2008;128(4):825-32.

2007

Limbourg A, Ploom M, Elligsen D, Sorensen I, Ziegelhoeffer T, Gossler A, Drexler H, Limbourg FP. Notch Ligand Delta-Like 1 Is Essential for Postnatal Arteriogenesis. Circ Res. 2007;100(3):363-71. Epub 2007/01/20.

Geffers I, Serth K, Chapman G, Jaekel R, Schuster-Gossler K, Cordes R, Sparrow DB, Kremmer E, Dunwoodie SL, Klein T, Gossler A. Divergent Functions and Distinct Localization of the Notch Ligands Dll1 and Dll3 in Vivo. J Cell Biol. 2007;178(3):465-76.

Cheng HT, Kim M, Valerius MT, Surendran K, Schuster-Gossler K, Gossler A, McMahon AP, Kopan R. Notch2, but Not Notch1, Is Required for Proximal Fate Acquisition in the Mammalian Nephron. Development. 2007;134(4):801-11. Epub 2007/01/19.

Beckers A, Alten L, Viebahn C, Andre P, Gossler A. The Mouse Homeobox Gene Noto Regulates Node Morphogenesis, Notochordal Ciliogenesis, and Left Right Patterning. Proc Natl Acad Sci U S A. 2007;104(40):15765-70.

Schuster-Gossler K, Cordes R, Gossler A. Premature Myogenic Differentiation and Depletion of Progenitor Cells Cause Severe Muscle Hypotrophy in Delta1 Mutants. Proc Natl Acad Sci U S A. 2007;104(2):537-42.

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