Distinct morphogenetic functions of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion.

The small GTPases of the Rac/Rho/Cdc42 subfamily are implicated in actin cytoskeleton-membrane interaction in mammalian cells and budding yeast. The in vivo functions of these GTPases in multicellular organisms are not known. We have cloned Drosophila homologs of rac and CDC42, Drac1, and Dcdc42. They share 70% amino acid sequence identity with each other, and both are highly expressed in the nervous system and mesoderm during neuronal and muscle differentiation, respectively. We expressed putative constitutively active and dominant-negative Drac1 proteins in these tissues. When expressed in neurons, Drac1 mutant proteins cause axon outgrowth defects in peripheral neurons without affecting dendrites. When expressed in muscle precursors, they cause complete failure of, or abnormality in, myoblast fusion. Expressions of analogous mutant Dcdc42 proteins cause qualitatively distinct morphological defects, suggesting that similar GTPases in the same subfamily have unique roles in morphogenesis.

[1]  K. Yao,et al.  Neural Specificity of elav Expression: Defining a Drosophila Promoter for Directing Expression to the Nervous System , 1994, Journal of neurochemistry.

[2]  D. Gell,et al.  The cell adhesion molecule, connectin, and the development of the Drosophila neuromuscular system. , 1994, Journal of cell science.

[3]  Harold Weintraub,et al.  The MyoD family and myogenesis: Redundancy, networks, and thresholds , 1993, Cell.

[4]  D. Bentley,et al.  Accumulation of actin in subsets of pioneer growth cone filopodia in response to neural and epithelial guidance cues in situ , 1993, The Journal of cell biology.

[5]  I. Herskowitz,et al.  BUD2 encodes a GTPase-activating protein for Budl/Rsrl necessary for proper bud-site selection in yeast , 1993, Nature.

[6]  J. Littleton,et al.  Expression of synaptotagmin in Drosophila reveals transport and localization of synaptic vesicles to the synapse. , 1993, Development.

[7]  C. Goodman,et al.  Genes that control neuromuscular specificity in Drosophila , 1993, Cell.

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

[9]  Y. Jan,et al.  Cell interactions and gene interactions in peripheral neurogenesis. , 1993, Genes & development.

[10]  C. Goodman,et al.  Mutations affecting growth cone guidance in drosophila: Genes necessary for guidance toward or away from the midline , 1993, Neuron.

[11]  R. Cripps,et al.  Molecular genetic analysis of muscle development, structure, and function in Drosophila. , 1993, International review of cytology.

[12]  B. Tocqué,et al.  The Saccharomyces cerevisiae SDC25 C-domain gene product overcomes the dominant inhibitory activity of Ha-Ras Asn-17. , 1993, Molecular and cellular biology.

[13]  K. Kosik,et al.  Suppression of MAP2 in cultured cerebeller macroneurons inhibits minor neurite formation , 1992, Neuron.

[14]  C. Goodman,et al.  Connectin: A homophilic cell adhesion molecule expressed on a subset of muscles and the motoneurons that innervate them in Drosophila , 1992, Cell.

[15]  Anne J. Ridley,et al.  The small GTP-binding protein rac regulates growth factor-induced membrane ruffling , 1992, Cell.

[16]  Anne J. Ridley,et al.  The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors , 1992, Cell.

[17]  J. Sanes,et al.  Roles for the integrin VLA-4 and its counter receptor VCAM-1 in myogenesis , 1992, Cell.

[18]  P. Sternberg,et al.  Analysis of dominant-negative mutations of the Caenorhabditis elegans let-60 ras gene. , 1991, Genes & development.

[19]  S. Aaronson,et al.  Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbloncogene product , 1991, Nature.

[20]  G. Rubin,et al.  Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase , 1991, Cell.

[21]  G. Rubin.  Signal transduction and the fate of the R7 photoreceptor in Drosophila. , 1991, Trends in genetics : TIG.

[22]  S. Powers,et al.  Functional cloning of BUD5, a CDC25-related gene from S. cerevisiae that can suppress a dominant-negative RAS2 mutant , 1991, Cell.

[23]  I. Herskowitz,et al.  Genetic control of bud site selection in yeast by a set of gene products that constitute a morphogenetic pathway , 1991, Cell.

[24]  D. Drubin.  Development of cell polarity in budding yeast , 1991, Cell.

[25]  I. Herskowitz,et al.  Yeast BUD5, encoding a putative GDP-GTP exchange factor, is necessary for bud site selection and interacts with bud formation gene BEM1 , 1991, Cell.

[26]  L. Hunt,et al.  A region of proto-dbl essential for its transforming activity shows sequence similarity to a yeast cell cycle gene, CDC24, and the human breakpoint cluster gene, bcr. , 1991, The New biologist.

[27]  Frank McCormick,et al.  The GTPase superfamily: conserved structure and molecular mechanism , 1991, Nature.

[28]  H. Horvitz,et al.  Caenorhabditis elegans ras gene let-60 acts as a switch in the pathway of vulval induction , 1990, Nature.

[29]  M. Bate,et al.  Expression of a MyoD family member prefigures muscle pattern in Drosophila embryos. , 1990, Genes & development.

[30]  R. Cerione,et al.  Molecular cloning of the gene for the human placental GTP-binding protein Gp (G25K): identification of this GTP-binding protein as the human homolog of the yeast cell-division-cycle protein CDC42. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Frasch,et al.  A new Drosophila homeo box gene is expressed in mesodermal precursor cells of distinct muscles during embryogenesis. , 1990, Genes & development.

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

[33]  J. Pringle,et al.  Molecular characterization of CDC42, a Saccharomyces cerevisiae gene involved in the development of cell polarity , 1990, The Journal of cell biology.

[34]  S. McElwee,et al.  A role for the Ca2(+)-dependent adhesion molecule, N-cadherin, in myoblast interaction during myogenesis. , 1990, Experimental cell research.

[35]  S. McElwee,et al.  A role for the neural cell adhesion molecule, NCAM, in myoblast interaction during myogenesis. , 1990, Developmental biology.

[36]  K. Kosik,et al.  Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons , 1990, Nature.

[37]  J. Pringle,et al.  Multicopy suppression of the cdc24 budding defect in yeast by CDC42 and three newly identified genes including the ras-related gene RSR1. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[38]  G M Bokoch,et al.  rac, a novel ras-related family of proteins that are botulinum toxin substrates. , 1989, The Journal of biological chemistry.

[39]  D. Bentley,et al.  Organization of cytoskeletal elements and organelles preceding growth cone emergence from an identified neuron in situ , 1989, The Journal of cell biology.

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

[41]  S. J. Smith,et al.  Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone , 1988, The Journal of cell biology.

[42]  G. Cooper,et al.  Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP , 1988, Molecular and cellular biology.

[43]  V. Hartenstein.  Development of Drosophila larval sensory organs: spatiotemporal pattern of sensory neurones, peripheral axonal pathways and sensilla differentiation , 1988 .

[44]  K. White,et al.  The locus elav of Drosophila melanogaster is expressed in neurons at all developmental stages. , 1988, Developmental biology.

[45]  G. Banker,et al.  The establishment of polarity by hippocampal neurons in culture , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[46]  G. Spizz,et al.  The oncogenic forms of N-ras or H-ras prevent skeletal myoblast differentiation , 1987, Molecular and cellular biology.

[47]  F. Eckstein,et al.  Inhibition of restriction endonuclease Nci I cleavage by phosphorothioate groups and its application to oligonucleotide-directed mutagenesis. , 1986, Nucleic acids research.

[48]  D. Bentley,et al.  Disoriented pathfinding by pioneer neurone growth cones deprived of filopodia by cytochalasin treatment , 1986, Nature.

[49]  D. Kiehart,et al.  Cytoplasmic myosin from Drosophila melanogaster , 1986, The Journal of cell biology.

[50]  D. Bar-Sagi,et al.  Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation , 1985, Cell.

[51]  S. Benzer,et al.  Monoclonal antibodies against the Drosophila nervous system. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[52]  G. Rubin,et al.  Transposition of cloned P elements into Drosophila germ line chromosomes. , 1982, Science.

[53]  Y. Jan,et al.  Antibodies to horseradish peroxidase as specific neuronal markers in Drosophila and in grasshopper embryos. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[54]  C. Nüsslein-Volhard,et al.  Mutations affecting segment number and polarity in Drosophila , 1980, Nature.