Pointed regulates an eye-specific transcriptional enhancer in the Drosophila hedgehog gene, which is required for the movement of the morphogenetic furrow

Drosophila development depends on stable boundaries between cellular territories, such as the embryonic parasegment boundaries and the compartment boundaries in the imaginal discs. Patterning in the compound eye is fundamentally different: the boundary is not stable, but moves (the morphogenetic furrow). Paradoxically, Hedgehog signaling is essential to both: Hedgehog is expressed in the posterior compartments in the embryo and in imaginal discs, and posterior to the morphogenetic furrow in the eye. Therefore, uniquely in the eye, cells receiving a Hedgehog signal will eventually produce the same protein. We report that the mechanism that underlies this difference is the special regulation of hedgehog (hh) transcription through the dual regulation of an eye specific enhancer. We show that this enhancer requires the Egfr/Ras pathway transcription factor Pointed. Recently, others have shown that this same enhancer also requires the eye determining transcription factor Sine oculis (So). We discuss these data in terms of a model for a combinatorial code of furrow movement.

[1]  Stephen S. Gisselbrecht,et al.  Ras Pathway Specificity Is Determined by the Integration of Multiple Signal-Activated and Tissue-Restricted Transcription Factors , 2000, Cell.

[2]  G. Struhl,et al.  Progression of the morphogenetic furrow in the Drosophila eye: the roles of Hedgehog, Decapentaplegic and the Raf pathway. , 1999, Development.

[3]  W. Gehring,et al.  Identification of functional sine oculis motifs in the autoregulatory element of its own gene, in the eyeless enhancer and in the signalling gene hedgehog , 2005, Development.

[4]  R. Carthew,et al.  Overlapping Activators and Repressors Delimit Transcriptional Response to Receptor Tyrosine Kinase Signals in the Drosophila Eye , 2000, Cell.

[5]  W. Fu,et al.  Deciphering synergistic and redundant roles of Hedgehog, Decapentaplegic and Delta that drive the wave of differentiation in Drosophila eye development , 2003, Development.

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

[7]  R. Cagan,et al.  Notch is required for successive cell decisions in the developing Drosophila retina. , 1989, Genes & development.

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

[9]  P. Lawrence,et al.  Compartments in Animal Development , 1979 .

[10]  M. Freeman,et al.  Pointed and Tramtrack69 establish an EGFR-dependent transcriptional switch to regulate mitosis , 2002, Nature Cell Biology.

[11]  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.

[12]  G. Rubin,et al.  Structural and functional comparisons of the Drosophila virilis and Drosophila melanogaster rough genes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[13]  N E Baker,et al.  Role of the EGFR/Ras/Raf pathway in specification of photoreceptor cells in the Drosophila retina. , 2001, Development.

[14]  U. Heberlein,et al.  Role of decapentaplegic in initiation and progression of the morphogenetic furrow in the developing Drosophila retina. , 1997, Development.

[15]  K. Basler,et al.  Hedgehog signaling in Drosophila eye and limb development — conserved machinery, divergent roles? , 1997, Current Opinion in Neurobiology.

[16]  G. Mardon,et al.  senseless Repression of rough Is Required for R8 Photoreceptor Differentiation in the Developing Drosophila Eye , 2001, Neuron.

[17]  G M Rubin,et al.  wingless inhibits morphogenetic furrow movement in the Drosophila eye disc. , 1995, Development.

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

[19]  P. Lawrence,et al.  Homoeotic genes, compartments and cell determination in Drosophila , 1977, Nature.

[20]  C. Rieder,et al.  Greatwall kinase , 2004, The Journal of cell biology.

[21]  A. Tomlinson The cellular dynamics of pattern formation in the eye of Drosophila. , 1985, Journal of embryology and experimental morphology.

[22]  U. Heberlein,et al.  Mutual Regulation ofdecapentaplegicandhedgehogduring the Initiation of Differentiation in theDrosophilaRetina , 1998 .

[23]  N. Baker,et al.  Proneural function of neurogenic genes in the developing Drosophila eye , 1997, Current Biology.

[24]  Lawrence Lum,et al.  The Hedgehog Response Network: Sensors, Switches, and Routers , 2004, Science.

[25]  J. Hooper Distinct pathways for autocrine and paracrine Wingless signalling inDrosophila embryos , 1994, Nature.

[26]  B. Dickson Nuclear factors in sevenless signalling. , 1995, Trends in genetics : TIG.

[27]  T. Tabata,et al.  Segmentation of the Drosophila embryo. , 1993, Current opinion in genetics & development.

[28]  Antonio Baonza,et al.  A primary role for the epidermal growth factor receptor in ommatidial spacing in the Drosophila eye , 2001, Current Biology.

[29]  R. Mann,et al.  Legs, Eyes, or Wings--Selectors and Signals Make the Difference , 2001, Science.

[30]  Ernst Hafen,et al.  The ETS domain protein Pointed-P2 is a target of MAP kinase in the Sevenless signal transduction pathway , 1994, Nature.

[31]  J P Kumar,et al.  Dissecting the roles of the Drosophila EGF receptor in eye development and MAP kinase activation. , 1998, Development.

[32]  Rui Chen,et al.  Mechanism of hedgehog signaling during Drosophila eye development , 2003, Development.

[33]  A. Mccarthy Development , 1996, Current Opinion in Neurobiology.

[34]  Mary Ellen Lane,et al.  Function of protein kinase A in hedgehog signal transduction and Drosophila imaginal disc development , 1995, Cell.

[35]  P. Lawrence The cellular basis of segmentation in insects , 1981, Cell.

[36]  P. O’Farrell,et al.  The making of a maggot: patterning the Drosophila embryonic epidermis. , 1994, Current opinion in genetics & development.

[37]  Gerald M. Rubin,et al.  The TGFβ homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina , 1993, Cell.

[38]  E. Hafen,et al.  Hedgehog directly controls initiation and propagation of retinal differentiation in the Drosophila eye. , 1997, Genes & development.

[39]  H. Muller Further studies on the nature and causes of gene mutations. , 1932 .

[40]  D. Rio,et al.  Identification and analysis of a hyperactive mutant form of Drosophila P-element transposase. , 2002, Genetics.

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

[42]  G. Rubin,et al.  Regulation of the complex pattern of sevenless expression in the developing Drosophila eye. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Y. Li,et al.  Hedgehog activates the EGF receptor pathway during Drosophila head development. , 1999, Development.

[44]  E. B. Lewis,et al.  The Theory and Application of a New Method of Detecting Chromosomal Rearrangements in Drosophila melanogaster , 1954 .

[45]  G. Rubin,et al.  Analysis of the enhancer element that controls expression of sevenless in the developing Drosophila eye. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  E. Hafen,et al.  The spatial and temporal expression pattern of sevenless is exclusively controlled by gene‐internal elements. , 1989, The EMBO journal.

[47]  N. Baker,et al.  Evolution of proneural atonal expression during distinct regulatory phases in the developing Drosophila eye , 1996, Current Biology.

[48]  A. Tomlinson,et al.  Cellular interactions in the developing Drosophila eye. , 1988, Development.

[49]  G. Struhl A blastoderm fate map of compartments and segments of the Drosophila head. , 1981, Developmental biology.

[50]  A. Jarman,et al.  Drosophila atonal controls photoreceptor R8-specific properties and modulates both receptor tyrosine kinase and Hedgehog signalling. , 2000, Development.

[51]  D. Ready,et al.  Neuronal differentiation in Drosophila ommatidium. , 1987, Developmental biology.

[52]  S. Benzer,et al.  Development of the Drosophila retina, a neurocrystalline lattice. , 1976, Developmental biology.

[53]  M. Bate,et al.  The development of Drosophila melanogaster , 1993 .

[54]  M. Akam,et al.  The molecular basis for metameric pattern in the Drosophila embryo. , 1987, Development.

[55]  G. Mardon,et al.  Signaling by the TGF-beta homolog decapentaplegic functions reiteratively within the network of genes controlling retinal cell fate determination in Drosophila. , 1999, Development.

[56]  J. Royet,et al.  hedgehog, wingless and orthodenticle specify adult head development in Drosophila. , 1996, Development.

[57]  H. Bellen,et al.  Senseless, a Zn Finger Transcription Factor, Is Necessary and Sufficient for Sensory Organ Development in Drosophila , 2000, Cell.

[58]  T. Lecuit,et al.  Mad acts downstream of Dpp receptors, revealing a differential requirement for dpp signaling in initiation and propagation of morphogenesis in the Drosophila eye. , 1996, Development.

[59]  A. Hidalgo The roles of engrailed. , 1996, Trends in genetics : TIG.

[60]  K. Basler,et al.  Hedgehog-dependent patterning in the Drosophila eye can occur in the absence of Dpp signaling. , 1996, Developmental biology.

[61]  K. Pennypacker,et al.  Mobility-Shift DNA-Binding Assay Using Gel Electrophoresis. , 1999, Methods in molecular medicine.

[62]  The Drosophila TGF alpha homolog Spitz acts in photoreceptor recruitment in the developing retina. , 1997, Development.

[63]  K. Moses,et al.  The Drosophila TGF alpha homolog Spitz acts in photoreceptor recruitment in the developing retina. , 1997, Development.

[64]  U. Heberlein,et al.  Mutual regulation of decapentaplegic and hedgehog during the initiation of differentiation in the Drosophila retina. , 1998, Developmental biology.

[65]  S. Buratowski,et al.  Mobility Shift DNA‐Binding Assay Using Gel Electrophoresis , 2001, Current protocols in pharmacology.

[66]  D. Strutt,et al.  Hedgehog is an indirect regulator of morphogenetic furrow progression in the Drosophila eye disc. , 1997, Development.

[67]  U. Heberlein,et al.  Retinal morphogenesis in Drosophila: hints from an eye-specific decapentaplegic allele. , 1997, Developmental genetics.

[68]  E. Hafen,et al.  Dynamics of Drosophila eye development and temporal requirements of sevenless expression. , 1989, Development.

[69]  N. Baker,et al.  Cell cycle withdrawal, progression, and cell survival regulation by EGFR and its effectors in the differentiating Drosophila eye. , 2003, Developmental cell.

[70]  J. Axelrod,et al.  The wingless signaling pathway is directly involved in Drosophila heart development. , 1996, Developmental biology.

[71]  J. Zhang,et al.  Ras1 signaling and transcriptional competence in the R7 cell of Drosophila. , 1996, Genes & development.

[72]  M. Dominguez,et al.  Dual role for Hedgehog in the regulation of the proneural gene atonal during ommatidia development. , 1999, Development.

[73]  G. Rubin,et al.  Genetic transformation of Drosophila with transposable element vectors. , 1982, Science.

[74]  P. Ingham,et al.  Boundaries and fields in early embryos , 1992, Cell.

[75]  S. Zipursky,et al.  The bride of sevenless and sevenless interaction: Internalization of a transmembrane ligand , 1992, Cell.

[76]  Y Sun,et al.  Transcriptional regulation of atonal during development of the Drosophila peripheral nervous system. , 1998, Development.

[77]  Norbert Perrimon,et al.  The genetic basis of patterned baldness in Drosophila , 1994, Cell.

[78]  K. Moses,et al.  Identification and characterization of autosomal genes that interact with glass in the developing Drosophila eye. , 1996, Genetics.

[79]  C. Klämbt,et al.  The Drosophila gene pointed encodes two ETS-like proteins which are involved in the development of the midline glial cells. , 1993, Development.

[80]  Ian W Duncan,et al.  Transvection effects in Drosophila. , 2002, Annual review of genetics.

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

[82]  I. Rebay,et al.  Signal integration during development: Insights from the Drosophila eye , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[83]  K. Moses,et al.  Expression of evolutionarily conserved eye specification genes during Drosophila embryogenesis , 2001, Development Genes and Evolution.

[84]  W. Gehring,et al.  Differential interactions of eyeless and twin of eyeless with the sine oculis enhancer. , 2002, Development.

[85]  C. Klämbt,et al.  Genetic dissection of pointed, a Drosophila gene encoding two ETS-related proteins. , 1993, Genetics.

[86]  Gerald M. Rubin,et al.  The activities of two Ets-related transcription factors required for drosophila eye development are modulated by the Ras/MAPK pathway , 1994, Cell.

[87]  T. J. Donohoe,et al.  Growth and differentiation in the Drosophila eye coordinated by hedgehog , 1995, Nature.

[88]  M. Mlodzik,et al.  Morphogenetic furrow initiation and progression during eye development in Drosophila: the roles of decapentaplegic, hedgehog and eyes absent. , 2000, Development.

[89]  J. Royet,et al.  Establishing primordia in the Drosophila eye-antennal imaginal disc: the roles of decapentaplegic, wingless and hedgehog. , 1997, Development.

[90]  Marek Mlodzik,et al.  The regulation of hedgehog and decapentaplegic during Drosophila eye imaginal disc development , 1996, Mechanisms of Development.

[91]  B. V. Shyamala,et al.  A positive role for patched-smoothened signaling in promoting cell proliferation during normal head development in Drosophila. , 2002, Development.

[92]  G. Rubin,et al.  dachshund encodes a nuclear protein required for normal eye and leg development in Drosophila. , 1994, Development.

[93]  S. Carroll,et al.  Molecular mechanisms of selector gene function and evolution. , 2002, Current opinion in genetics & development.

[94]  K. Moses,et al.  Wingless and patched are negative regulators of the morphogenetic furrow and can affect tissue polarity in the developing Drosophila compound eye. , 1995, Development.

[95]  U. Heberlein,et al.  Mechanisms of drosophila retinal morphogenesis: The virtues of being progressive , 1995, Cell.

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

[97]  D. Strutt,et al.  Regulation of furrow progression in the Drosophila eye by cAMP-dependent protein kinase A , 1995, Nature.

[98]  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.

[99]  J. Mohler Requirements for hedgehog, a segmental polarity gene, in patterning larval and adult cuticle of Drosophila. , 1988, Genetics.

[100]  G. Rubin,et al.  Signal transduction downstream from Ras in Drosophila. , 1997, Cold Spring Harbor symposia on quantitative biology.

[101]  N. Bonini,et al.  Functional analysis of an eye enhancer of the Drosophila eyes absent gene: differential regulation by eye specification genes. , 2000, Developmental biology.