A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing.

The secreted protein Hedgehog (Hh) transmits a signal from posterior to anterior cells that is essential for limb development in insects and vertebrates. In Drosophila, Hh has been thought to act primarily to induce localized expression of Decapentaplegic and Wingless which in turn relay patterning cues at long range. We report here that Hh plays an additional role in patterning the wing. By replacing endogenous Hh activity with that of a membrane-tethered form of Hh, we show that Hh acts directly to pattern the central region of the wing, in addition to its role as an inducer of Dpp. Comparing the biological activities of secreted and membrane-tethered Hh provides evidence that Hh forms a local concentration gradient and functions as a concentration-dependent morphogen in the fly wing.

[1]  P. Ingham,et al.  smoothened encodes a receptor-like serpentine protein required for hedgehog signalling , 1996, Nature.

[2]  S. Cohen,et al.  Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing , 1996, Nature.

[3]  P. Ingham,et al.  Role of the Drosophila patched gene in positional signalling , 1991, Nature.

[4]  M. Noll,et al.  The Drosophila smoothened Gene Encodes a Seven-Pass Membrane Protein, a Putative Receptor for the Hedgehog Signal , 1996, Cell.

[5]  K. G. Coleman,et al.  Expression of engrailed proteins in arthropods, annelids, and chordates. , 1989, Cell.

[6]  G. Rubin,et al.  cAMP-dependent protein kinase and hedgehog act antagonistically in regulating decapentaplegic transcription in drosophila imaginal discs , 1995, Cell.

[7]  Stephen C. Ekker,et al.  The product of hedgehog autoproteolytic cleavage active in local and long-range signalling , 1995, Nature.

[8]  P. Ingham,et al.  Quantitative effects of hedgehog and decapentaplegic activity on the patterning of the Drosophila wing , 1995, Current Biology.

[9]  T. Kornberg,et al.  Proteolysis That Is Inhibited by Hedgehog Targets Cubitus interruptus Protein to the Nucleus and Converts It to a Repressor , 1997, Cell.

[10]  J. Mullor,et al.  Hedgehog activity, independent of decapentaplegic, participates in wing disc patterning. , 1997, Development.

[11]  G. Struhl,et al.  Dual Roles for Patched in Sequestering and Transducing Hedgehog , 1996, Cell.

[12]  Thomas Lecuit,et al.  Proximal–distal axis formation in the Drosophila leg , 1997, Nature.

[13]  A. Hidalgo.  Three distinct roles for the engrailed gene in Drosophila wing development , 1994, Current Biology.

[14]  Eugene V Koonin,et al.  Hedgehog Patterning Activity: Role of a Lipophilic Modification Mediated by the Carboxy-Terminal Autoprocessing Domain , 1996, Cell.

[15]  D. Strutt,et al.  Ommatidial polarity in the Drosophila eye is determined by the direction of furrow progression and local interactions. , 1995, Development.

[16]  P. Beachy,et al.  Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development , 1996, Science.

[17]  G. Struhl,et al.  Protein kinase A and hedgehog signaling in drosophila limb development , 1995, Cell.

[18]  C. Neumann,et al.  Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. , 1997, Development.

[19]  J. J. Lee,et al.  Autoproteolysis in hedgehog protein biogenesis. , 1994, Science.

[20]  S. DiNardo,et al.  Drosophila hedgehog acts as a morphogen in cellular patterning , 1994, Cell.

[21]  W. Gelbart,et al.  An extensive 3' cis-regulatory region directs the imaginal disk expression of decapentaplegic, a member of the TGF-beta family in Drosophila. , 1991, Development.

[22]  C. Tabin,et al.  Regulation of patched by sonic hedgehog in the developing neural tube. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  C. Tabin,et al.  Sonic hedgehog mediates the polarizing activity of the ZPA , 1993, Cell.

[24]  S. Cohen,et al.  Distinguishable functions for engrailed and Invected in anterior–posterior patterning in the Drosopila wing , 1995, Nature.

[25]  E. Sánchez-Herrero,et al.  The function of engrailed and the specification of Drosophila wing pattern. , 1995, Development.

[26]  Konrad Basler,et al.  Compartment boundaries and the control of Drosopfiffa limb pattern by hedgehog protein , 1994, Nature.

[27]  M. Scott,et al.  The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog , 1996, Nature.

[28]  G. Struhl,et al.  Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. , 1995, Development.

[29]  D. Slusarski,et al.  Mutations that alter the timing and pattern of cubitus interruptus gene expression in Drosophila melanogaster. , 1995, Genetics.

[30]  K. Moses,et al.  The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye , 1993, Cell.

[31]  A. McMahon,et al.  Distribution of Sonic hedgehog peptides in the developing chick and mouse embryo. , 1995, Development.

[32]  T. Jessell,et al.  Pax6 Controls Progenitor Cell Identity and Neuronal Fate in Response to Graded Shh Signaling , 1997, Cell.

[33]  F. Díaz-Benjumea,et al.  Serrate signals through Notch to establish a Wingless-dependent organizer at the dorsal/ventral compartment boundary of the Drosophila wing. , 1995, Development.

[34]  E. Marin,et al.  The spalt gene links the A/P compartment boundary to a linear adult structure in the Drosophila wing. , 1997, Development.

[35]  T. Kornberg,et al.  Analysis of cubitus interruptus regulation in Drosophila embryos and imaginal disks. , 1995, Development.

[36]  C. Tabin,et al.  Biochemical evidence that Patched is the Hedgehog receptor , 1996, Nature.

[37]  Konrad Basler,et al.  Organizing activity of wingless protein in Drosophila , 1993, Cell.

[38]  T. Jessell,et al.  Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis , 1995, Cell.

[39]  G. Struhl,et al.  Direct and Long-Range Action of a DPP Morphogen Gradient , 1996, Cell.

[40]  A. Taylor,et al.  Secretion of the amino-terminal fragment of the Hedgehog protein is necessary and sufficient for hedgehog signalling in Drosophila , 1995, Current Biology.

[41]  P. Ingham.  Localized hedgehog activity controls spatial limits of wingless transcription in the Drosophila embryo , 1993, Nature.

[42]  S. Zipursky,et al.  Induction of Drosophila eye development by decapentaplegic. , 1997, Development.

[43]  T. Tabata,et al.  Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs , 1994, Cell.

[44]  P. Beachy,et al.  Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog , 1992, Cell.

[45]  P. Lawrence,et al.  Hedgehog acts by distinct gradient and signal relay mechanisms to organise cell type and cell polarity in the Drosophila abdomen. , 1997, Development.

[46]  E. Sánchez-Herrero,et al.  The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development. , 1994, The EMBO journal.

[47]  R. L. Johnson,et al.  patched overexpression alters wing disc size and pattern: transcriptional and post-transcriptional effects on hedgehog targets. , 1995, Development.

[48]  M. Tessier-Lavigne,et al.  Long-range sclerotome induction by sonic hedgehog: Direct role of the amino-terminal cleavage product and modulation by the cyclic AMP signaling pathway , 1995, Cell.

[49]  R. Barrio,et al.  A gene complex acting downstream of dpp in Drosophila wing morphogenesis , 1996, Nature.

[50]  C. K. Motzny,et al.  The Drosophila cubitus interruptus protein and its role in the wingless and hedgehog signal transduction pathways , 1995, Mechanisms of Development.

[51]  Konrad Basler,et al.  Sending and Receiving the Hedgehog Signal: Control by the Drosophila Gli Protein Cubitus interruptus , 1996, Science.

[52]  W. Gelbart,et al.  Signaling through both type I DPP receptors is required for anterior-posterior patterning of the entire Drosophila wing. , 1997, Development.

[53]  G. Struhl,et al.  Direct and Long-Range Action of a Wingless Morphogen Gradient , 1996, Cell.

[54]  S. Blair,et al.  Engrailed expression in the anterior lineage compartment of the developing wing blade of Drosophila. , 1992, Development.

[55]  K. Basler,et al.  Dpp receptors are autonomously required for cell proliferation in the entire developing Drosophila wing. , 1996, Development.

[56]  P. Lawrence,et al.  Hedgehog organises the pattern and polarity of epidermal cells in the Drosophila abdomen. , 1997, Development.

[57]  T. Tabata,et al.  Creating a Drosophila wing de novo, the role of engrailed, and the compartment border hypothesis. , 1995, Development.

[58]  Manuel Calleja,et al.  Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing , 1996, Nature.

[59]  P. Ingham,et al.  The Drosophila segment polarity gene patched is involved in a position-signalling mechanism in imaginal discs. , 1990, Development.

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

[61]  Johan Ericson,et al.  Two Critical Periods of Sonic Hedgehog Signaling Required for the Specification of Motor Neuron Identity , 1996, Cell.