The Drosophila spitz gene encodes a putative EGF-like growth factor involved in dorsal-ventral axis formation and neurogenesis.

We describe the molecular characterization of the Drosophila gene spitz (spi), which encodes a putative 26-kD, EGF-like transmembrane protein that is structurally similar to TGF-alpha. Temporal and spatial expression patterns of spi transcripts indicate that spi is expressed throughout the embryo. Examination of mutant embryos reveals that spi is involved in a number of unrelated developmental choices, for example, dorsal-ventral axis formation, glial migration, sensory organ determination, and muscle development. We propose that spi may act as a ligand for cell-specific receptors, possibly rhomboid and/or the Drosophila EGF receptor homolog.

[1]  J. Devereux,et al.  A comprehensive set of sequence analysis programs for the VAX , 1984, Nucleic Acids Res..

[2]  M. Leptin,et al.  Cell shape changes during gastrulation in Drosophila. , 1990, Development.

[3]  Christian Klämbt,et al.  The midline of the drosophila central nervous system: A model for the genetic analysis of cell fate, cell migration, and growth cone guidance , 1991, Cell.

[4]  Stephen M. Mount,et al.  A catalogue of splice junction sequences. , 1982, Nucleic acids research.

[5]  G. Shaw,et al.  A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation , 1986, Cell.

[6]  W. Gelbart,et al.  Decapentaplegic transcripts are localized along the dorsal‐ventral axis of the Drosophila embryo. , 1987, The EMBO journal.

[7]  G von Heijne,et al.  Patterns of amino acids near signal-sequence cleavage sites. , 1983, European journal of biochemistry.

[8]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[9]  Kathleen Weston,et al.  The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch , 1988, Nature.

[10]  C. Goodman,et al.  Sequence analysis and neuronal expression of fasciclin I in grasshopper and drosophila , 1988, Cell.

[11]  S. Roth,et al.  The polarity of the dorsoventral axis in the drosophila embryo is defined by an extracellular signal , 1991, Cell.

[12]  R. J. Fleming,et al.  The gene Serrate encodes a putative EGF-like transmembrane protein essential for proper ectodermal development in Drosophila melanogaster. , 1990, Genes & development.

[13]  J. Campos-Ortega,et al.  The neurogenic gene Delta of Drosophila melanogaster is expressed in neurogenic territories and encodes a putative transmembrane protein with EGF‐like repeats , 1987, The EMBO journal.

[14]  Y. Jan,et al.  rhomboid, a gene required for dorsoventral axis establishment and peripheral nervous system development in Drosophila melanogaster. , 1990, Genes & development.

[15]  B. Shilo,et al.  Dissection of the faint little ball (flb) phenotype: determination of the development of the Drosophila central nervous system by early interactions in the ectoderm. , 1992, Development.

[16]  Y. Jan,et al.  Transformation of sensory organs by Mutations of the cut locus of D. melanogaster , 1987, Cell.

[17]  J. Hirsh,et al.  Molecular mapping of a gene cluster flanking the Drosophila Dopa decarboxylase gene. , 1984, Genetics.

[18]  F. Studier,et al.  Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes. , 1986, Journal of molecular biology.

[19]  C. Nüsslein-Volhard,et al.  A group of genes required for pattern formation in the ventral ectoderm of the Drosophila embryo. , 1988, Genes & development.

[20]  S. Benzer,et al.  Neuronal development in the drosophila retina: Monoclonal antibodies as molecular probes , 1984, Cell.

[21]  M. Ashburner,et al.  Genetic resistance to viral infection: the molecular cloning of a Drosophila gene that restricts infection by the rhabdovirus sigma. , 1989, Genetics.

[22]  Y. Jan,et al.  The maternal sex determination gene daughterless has zygotic activity necessary for the formation of peripheral neurons in Drosophila. , 1988, Genes & development.

[23]  M. Hauser,et al.  Aromaticity at position 37 in human epidermal growth factor is not obligatory for activity , 1991, Molecular and cellular biology.

[24]  C. P. Bishop,et al.  The genetics of dopa decarboxylase in Drosophila melanogaster. IV. The genetics and cytology of the 37B10-37D1 region. , 1981, Chromosoma.

[25]  N. Proudfoot,et al.  3′ Non-coding region sequences in eukaryotic messenger RNA , 1976, Nature.

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

[27]  K. Fechtel,et al.  Delta, a Drosophila neurogenic gene, is transcriptionally complex and encodes a protein related to blood coagulation factors and epidermal growth factor of vertebrates. , 1988, Genes & development.

[28]  D. L. Weeks,et al.  A maternal mRNA localized to the vegetal hemisphere in xenopus eggs codes for a growth factor related to TGF-β , 1987, Cell.

[29]  B Z Shilo,et al.  Localization of the DER/flb protein in embryos: implications on the faint little ball lethal phenotype. , 1990, Development.

[30]  S. Artavanis-Tsakonas,et al.  Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats , 1985, Cell.

[31]  R. Derynck,et al.  Transforming growth factor‐α , 1990, Molecular reproduction and development.

[32]  C. Wilson,et al.  P-element-mediated enhancer detection: an efficient method for isolating and characterizing developmentally regulated genes in Drosophila. , 1989, Genes & development.

[33]  G. Rubin,et al.  Analysis of P transposable element functions in drosophila , 1984, Cell.

[34]  W. Gelbart,et al.  A transcript from a Drosophila pattern gene predicts a protein homologous to the transforming growth factor-β family , 1987, Nature.

[35]  G. Rubin,et al.  Tissue specificity of Drosophila P element transposition is regulated at the level of mRNA splicing , 1986, Cell.

[36]  Stephen T. Crews,et al.  Molecular genetics of the single-minded locus: A gene involved in the development of the Drosophila nervous system , 1988, Cell.

[37]  I. Campbell,et al.  Structure-function relationships in epidermal growth factor (egf) and transforming growth factor-alpha (TGF-α) , 1990 .

[38]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[39]  E. Chen,et al.  Human transforming growth factor-α: Precursor structure and expression in E. coli , 1984, Cell.

[40]  R. Steward.  Dorsal, an embryonic polarity gene in Drosophila, is homologous to the vertebrate proto-oncogene, c-rel. , 1987, Science.

[41]  H. L. Carson,et al.  The Genetics and Biology of Drosophila , 1976, Heredity.

[42]  M. Kirschner,et al.  Synergistic induction of mesoderm by FGF and TGF-β and the identification of an mRNA coding for FGF in the early xenopus embryo , 1987, Cell.

[43]  Y. Jan,et al.  Neurogenesis of the peripheral nervous system in Drosophila embryos: DNA replication patterns and cell lineages , 1989, Neuron.

[44]  J. Smith,et al.  A mesoderm-inducing factor is produced by Xenopus cell line. , 1987, Development.

[45]  R. Doolittle,et al.  A simple method for displaying the hydropathic character of a protein. , 1982, Journal of molecular biology.

[46]  V. Pirrotta.  Vectors for P-mediated transformation in Drosophila. , 1988, Biotechnology.

[47]  W. Gelbart,et al.  The decapentaplegic gene is required for dorsal-ventral patterning of the Drosophila embryo. , 1987, Genes & development.

[48]  D. Lindsley,et al.  Genetic variations of Drosophila melanogaster , 1967 .

[49]  J. Smith,et al.  Graded changes in dose of a Xenopus activin A homologue elicit stepwise transitions in embryonic cell fate , 1990, Nature.

[50]  T. Uemura,et al.  Searching for pattern and mutation in the Drosophila genome with a P-lacZ vector. , 1989, Genes & development.

[51]  A. Feinberg,et al.  A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. , 1983, Analytical biochemistry.

[52]  M. Bownes,et al.  Drosophila: A practical approach: edited by D. B. Roberts IRL Press, 1986. £26.00/$47.00 (xix + 295 pages) ISBN 0 94746 66 7 , 1987 .

[53]  D. Lindsley,et al.  The Genome of Drosophila Melanogaster , 1992 .

[54]  G. I. Bell,et al.  Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization. , 1986, Nucleic acids research.

[55]  B. Moss,et al.  Complete Nucleotide Sequences of Two Adjacent Early Vaccinia Virus Genes Located Within the Inverted Terminal Repetition , 1982, Journal of virology.

[56]  G. Shaw,et al.  Translational blockade imposed by cytokine-derived UA-rich sequences. , 1989, Science.

[57]  D. Twardzik,et al.  Vaccinia virus encodes a polypeptide homologous to epidermal growth factor and transforming growth factor , 1985, Nature.

[58]  M. Levine,et al.  Transcripts encoded by a homoeo box gene are restricted to dorsal tissues of Drosophila embryos , 1986, Nature.

[59]  Stephen T. Crews,et al.  The Drosophila single-minded gene encodes a nuclear protein with sequence similarity to the per gene product , 1988, Cell.

[60]  C. Disteche,et al.  The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity , 1990, Molecular and cellular biology.

[61]  T. Schüpbach,et al.  The maternal ventralizing locus torpedo is allelic to faint little ball, an embryonic lethal, and encodes the Drosophila EGF receptor homolog , 1989, Cell.

[62]  D. Melton,et al.  Pattern formation during animal development. , 1991, Science.

[63]  A. C. Crossley,et al.  morphology and development of the Drosophila muscular system , 1978 .

[64]  B. Shilo,et al.  The Drosophila EGF receptor gene homolog: Conservation of both hormone binding and kinase domains , 1985, Cell.

[65]  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.

[66]  M. Noll,et al.  Structure of the segmentation gene paired and the Drosophila PRD gene set as part of a gene network , 1986, Cell.

[67]  Y. Jan,et al.  Identification and characterization of a neuron-specific nuclear antigen in Drosophila. , 1988, Science.

[68]  M. Klagsbrun,et al.  A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF , 1991, Science.

[69]  B. Shilo,et al.  The Drosophila EGF receptor homolog (DER) gene is allelic to faint little ball, a locus essential for embryonic development , 1989, Cell.

[70]  D. Lipman,et al.  Improved tools for biological sequence comparison. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[71]  G M Rubin,et al.  Isolation and expression of scabrous, a gene regulating neurogenesis in Drosophila. , 1990, Genes & development.

[72]  W. Gelbart,et al.  Mobilization of hobo elements residing within the decapentaplegic gene complex: Suggestion of a new hybrid dysgenesis system in Drosophila melanogaster , 1987, Cell.

[73]  J. Massagué,et al.  Transforming growth factor-alpha. A model for membrane-anchored growth factors. , 1990, The Journal of biological chemistry.

[74]  J. Hooper,et al.  Homeotic gene function in the muscles of Drosophila larvae , 1986, The EMBO journal.

[75]  D. Cavener,et al.  Comparison of the consensus sequence flanking translational start sites in Drosophila and vertebrates. , 1987, Nucleic acids research.

[76]  W. Fischer,et al.  Structure, expression and function of a schwannoma-derived growth factor , 1990, Nature.