The transmembrane protein Kon-tiki couples to Dgrip to mediate myotube targeting in Drosophila.

Directed cell migration and target recognition are critical for the development of both the nervous and muscular systems. Molecular mechanisms that control these processes in the nervous system have been intensively studied, whereas those that act during muscle development are still largely uncharacterized. Here we identify a transmembrane protein, Kon-tiki (Kon), that mediates myotube target recognition in the Drosophila embryo. Kon is expressed in a specific subset of myotubes and is required autonomously for these myotubes to recognize their tendon cell targets and to establish a stable connection. Kon is enriched at myotube tips during targeting and signals through the intracellular adaptor Dgrip in a conserved molecular pathway. Forced overexpression of Kon stimulates muscle motility. We propose that Kon promotes directed myotube migration and transduces a target-derived signal that initiates the formation of a stable connection.

[1]  R. Abagyan,et al.  Novel Anchorage of GluR2/3 to the Postsynaptic Density by the AMPA Receptor–Binding Protein ABP , 1998, Neuron.

[2]  B. Dickson.  Molecular Mechanisms of Axon Guidance , 2002, Science.

[3]  M. Frasch,et al.  The role of the NK-homeobox gene slouch (S59) in somatic muscle patterning. , 1999, Development.

[4]  M. Sheng,et al.  PDZ domains and the organization of supramolecular complexes. , 2001, Annual review of neuroscience.

[5]  Elizabeth H. Chen,et al.  Control of Myoblast Fusion by a Guanine Nucleotide Exchange Factor, Loner, and Its Effector ARF6 , 2003, Cell.

[6]  M. Bate,et al.  Segregation of myogenic lineages in Drosophila requires numb. , 1997, Development.

[7]  A. Nose,et al.  Regional specification of muscle progenitors in Drosophila: the role of the msh homeobox gene. , 1998, Development.

[8]  M. Alfenito,et al.  Contractile Proteins in Drosophila Development a , 1990, Annals of the New York Academy of Sciences.

[9]  D. Kiehart,et al.  zipper Nonmuscle myosin-II functions downstream of PS2 integrin in Drosophila myogenesis and is necessary for myofibril formation. , 2001, Developmental biology.

[10]  W. Stallcup,et al.  Chondroitin sulfate and cytoplasmic domain-dependent membrane targeting of the NG2 proteoglycan promotes retraction fiber formation and cell polarization. , 2001, Journal of cell science.

[11]  Manuela Schmidt,et al.  A glutamate receptor-interacting protein homolog organizes muscle guidance in Drosophila. , 2004, Genes & development.

[12]  C. Goodman,et al.  Slit Is the Midline Repellent for the Robo Receptor in Drosophila , 1999, Cell.

[13]  W. Stallcup,et al.  NG2 Proteoglycan Promotes Endothelial Cell Motility and Angiogenesis via Engagement of Galectin-3 and α3β1 Integrin , 2004 .

[14]  W. Stallcup,et al.  High-affinity Binding of Basic Fibroblast Growth Factor and Platelet-derived Growth Factor-AA to the Core Protein of the NG2 Proteoglycan* , 1999, The Journal of Biological Chemistry.

[15]  M. Bate,et al.  The embryonic development of larval muscles in Drosophila. , 1990, Development.

[16]  W. Stallcup.  The NG2 proteoglycan: Past insights and future prospects , 2002, Journal of neurocytology.

[17]  R. Reisfeld,et al.  Biosynthetic studies of proteoglycans in human melanoma cells with a monoclonal antibody to a core glycoprotein of chondroitin sulfate proteoglycans. , 1984, The Journal of biological chemistry.

[18]  B. Dickson,et al.  Crossing the Midline Roles and Regulation of Robo Receptors , 2000, Neuron.

[19]  J. Trotter,et al.  Cell-Surface Glycoprotein of Oligodendrocyte Progenitors Involved in Migration , 1999, The Journal of Neuroscience.

[20]  C. Nüsslein-Volhard,et al.  An F1 Genetic Screen for Maternal-Effect Mutations Affecting Embryonic Pattern Formation in Drosophila melanogaster , 2004, Genetics.

[21]  N. Patel,et al.  Imaging neuronal subsets and other cell types in whole-mount Drosophila embryos and larvae using antibody probes. , 1994, Methods in cell biology.

[22]  A. Rosenthal,et al.  A novel repeat in the melanoma‐associated chondroitin sulfate proteoglycan defines a new protein family , 2002, FEBS letters.

[23]  C. Goodman,et al.  commissureless Controls Growth Cone Guidance across the CNS Midline in Drosophila and Encodes a Novel Membrane Protein , 1996, Neuron.

[24]  A. Nishiyama,et al.  The expression of NG2 proteoglycan in the developing rat limb. , 1991, Development.

[25]  R. Huganir,et al.  Characterization of the Glutamate Receptor-Interacting Proteins GRIP1 and GRIP2 , 1999, The Journal of Neuroscience.

[26]  Marc Tessier-Lavigne,et al.  Roundabout Controls Axon Crossing of the CNS Midline and Defines a Novel Subfamily of Evolutionarily Conserved Guidance Receptors , 1998, Cell.

[27]  M. Bate,et al.  Mutations in a novel gene, myoblast city, provide evidence in support of the founder cell hypothesis for Drosophila muscle development. , 1995, Development.

[28]  F. Ruggiero,et al.  The Membrane-spanning Proteoglycan NG2 Binds to Collagens V and VI through the Central Nonglobular Domain of Its Core Protein* , 1997, The Journal of Biological Chemistry.

[29]  T. Hummel,et al.  Characterization of a novel Drosophila melanogaster galectin. Expression in developing immune, neural, and muscle tissues. , 2002, The Journal of biological chemistry.

[30]  D. Barritt,et al.  Cytoskeletal reorganization induced by engagement of the NG2 proteoglycan leads to cell spreading and migration. , 1999, Molecular biology of the cell.

[31]  R. Weinberg,et al.  Interaction between GRIP and Liprin-α/SYD2 Is Required for AMPA Receptor Targeting , 2002, Neuron.

[32]  K. Nave,et al.  The Proteoglycan NG2 Is Complexed with α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors by the PDZ Glutamate Receptor Interaction Protein (GRIP) in Glial Progenitor Cells , 2003, The Journal of Biological Chemistry.

[33]  R. Renkawitz-Pohl,et al.  β3 tubulin expression characterizes the differentiating mesodermal germ layer during Drosophila embryogenesis , 1988 .

[34]  Y. Jan,et al.  frazzled Encodes a Drosophila Member of the DCC Immunoglobulin Subfamily and Is Required for CNS and Motor Axon Guidance , 1996, Cell.

[35]  Julie H. Simpson,et al.  Switching Repulsion to Attraction: Changing Responses to Slit During Transition in Mesoderm Migration , 2001, Science.

[36]  Frank Schnorrer,et al.  Muscle building; mechanisms of myotube guidance and attachment site selection. , 2004, Developmental cell.

[37]  E. Suzuki,et al.  Postsynaptic filopodia in muscle cells interact with innervating motoneuron axons , 2000, Nature Neuroscience.

[38]  S. Zipursky,et al.  Retinal Axon Target Selection in Drosophila Is Regulated by a Receptor Protein Tyrosine Phosphatase , 1999, Neuron.

[39]  John B. Thomas,et al.  Axon routing across the midline controlled by the Drosophila Derailed receptor , 1999, Nature.

[40]  M. Martín-Bermudo,et al.  Integrins as mediators of morphogenesis in Drosophila. , 2000, Developmental biology.

[41]  K. VijayRaghavan,et al.  A central role for epidermal segment border cells in the induction of muscle patterning in the Drosophila embryo. , 1994, Development.

[42]  Y. Wen,et al.  Molecular basis of interaction between NG2 proteoglycan and galectin‐3 , 2006, Journal of cellular biochemistry.

[43]  N. Perrimon,et al.  Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. , 1993, Development.

[44]  Y. Yamaguchi,et al.  Expression of NG2 proteoglycan during endochondral and intramembranous ossification , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[45]  R. Huganir,et al.  GRASP-1 A Neuronal RasGEF Associated with the AMPA Receptor/GRIP Complex , 2000, Neuron.

[46]  R. Timpl,et al.  Binding of the NG2 Proteoglycan to Type VI Collagen and Other Extracellular Matrix Molecules* , 1996, The Journal of Biological Chemistry.

[47]  Manuela Schmidt,et al.  Complex interaction of Drosophila GRIP PDZ domains and Echinoid during muscle morphogenesis , 2006, The EMBO journal.

[48]  C. Goodman,et al.  The Molecular Biology of Axon Guidance , 1996, Science.

[49]  T Ochiya,et al.  PDGF (alpha)-receptor is unresponsive to PDGF-AA in aortic smooth muscle cells from the NG2 knockout mouse. , 1999, Journal of cell science.

[50]  John B. Thomas,et al.  derailed is required for muscle attachment site selection in Drosophila. , 1996, Development.

[51]  I. Guerrero,et al.  Targeted expression of the signaling molecule decapentaplegic induces pattern duplications and growth alterations in Drosophila wings. , 1994, The EMBO journal.