Notch signalling and the initiation of neural development in the Drosophila eye.

Neural determination in the Drosophila eye occurs progressively. A diffusible signal, Dpp, causes undetermined cells first to adopt a 'pre-proneural' state in which they are primed to start differentiating. A second signal is required to trigger the activation of the transcription factor Atonal, which causes the cells to initiate overt photoreceptor neurone differentiation. Both Dpp and the second signal are dependent on Hedgehog (Hh) signalling. Previous work has shown that the Notch signalling pathway also has a proneural role in the eye (as well as a later, opposite function when it restricts the number of cells becoming photoreceptors - a process of lateral inhibition). It is not clear how the early proneural role of Notch integrates with the other signalling pathways involved. We provide evidence that Notch activation by its ligand Delta is the second Hh-dependent signal required for neural determination. Notch activity normally only triggers Atonal expression in cells that have adopted the pre-proneural state induced by Dpp. We also report that Notch drives the transition from pre-proneural to proneural by downregulating two repressors of Atonal: Hairy and Extramacrochaetae.

[1]  E. Wieschaus,et al.  The Drosophila Gene brinker Reveals a Novel Mechanism of Dpp Target Gene Regulation , 1999, Cell.

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

[3]  G. Rubin,et al.  A putative Ras GTPase activating protein acts as a negative regulator of signaling by the Sevenless receptor tyrosine kinase , 1992, Cell.

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

[5]  T. Tabata,et al.  brinker is a target of Dpp in Drosophila that negatively regulates Dpp-dependent genes , 1999, Nature.

[6]  U. Heberlein,et al.  Role of the morphogenetic furrow in establishing polarity in the Drosophila eye. , 1995, Development.

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

[8]  N. Baker,et al.  The R8-photoreceptor equivalence group in Drosophila: fate choice precedes regulated Delta transcription and is independent of Notch gene dose , 1998, Mechanisms of Development.

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

[10]  R. W. Padgett,et al.  The Drosophila gene Medea demonstrates the requirement for different classes of Smads in dpp signaling. , 1998, Development.

[11]  S. Bray,et al.  Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. , 1997, Development.

[12]  S. Carroll,et al.  hairy gene function in the Drosophila eye: normal expression is dispensable but ectopic expression alters cell fates. , 1991, Development.

[13]  F. Turner,et al.  Relationships between complex Delta expression and the specification of retinal cell fates during Drosophila eye development , 1995, Mechanisms of Development.

[14]  Y Sun,et al.  Role of the proneural gene, atonal, in formation of Drosophila chordotonal organs and photoreceptors. , 1995, Development.

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

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

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

[18]  S. Artavanis-Tsakonas,et al.  The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands. , 1996, Development.

[19]  Yves Grau,et al.  atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system , 1993, Cell.

[20]  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.

[21]  C. Delidakis,et al.  A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex. , 1998, Development.

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

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

[24]  A. Garcı́a-Bellido,et al.  Relationships between extramacrochaetae and Notch signalling in Drosophila wing development. , 2000, Development.

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

[26]  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.

[27]  J. Modolell,et al.  Proneural clusters of achaete-scute expression and the generation of sensory organs in the Drosophila imaginal wing disc. , 1991, Genes & development.

[28]  S. Artavanis-Tsakonas,et al.  Notch Signaling : Cell Fate Control and Signal Integration in Development , 1999 .

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

[30]  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.

[31]  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.

[32]  J. Modolell,et al.  The Drosophila extramacrochaetae locus, an antagonist of proneural genes that, like these genes, encodes a helix-loop-helix protein , 1990, Cell.

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

[34]  G. Rubin,et al.  Analysis of genetic mosaics in developing and adult Drosophila tissues. , 1993, Development.

[35]  M. Freeman,et al.  Cell determination strategies in the Drosophila eye. , 1997, Development.

[36]  J. Hudson,et al.  The Drosophila Medea gene is required downstream of dpp and encodes a functional homolog of human Smad4. , 1998, Development.

[37]  Yuh Nung Jan,et al.  atonal is the proneural gene for Drosophila photoreceptors , 1994, Nature.

[38]  Kwang-Wook Choi,et al.  Fringe is essential for mirror symmetry and morphogenesis in the Drosophila eye , 1998, Nature.

[39]  T. L. Jacobsen,et al.  Feedback regulation is central to Delta-Notch signalling required for Drosophila wing vein morphogenesis. , 1997, Development.

[40]  S. Zipursky,et al.  Atonal, rough and the resolution of proneural clusters in the developing Drosophila retina. , 1996, Development.

[41]  A. Garcı́a-Bellido,et al.  Notch signaling directly controls cell proliferation in the Drosophila wing disc. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[42]  N. Baker,et al.  Proneural enhancement by Notch overcomes Suppressor-of-Hairless repressor function in the developing Drosophila eye , 2001, Current Biology.

[43]  J. Posakony,et al.  extramacrochaetae, a negative regulator of sensory organ development in Drosophila, defines a new class of helix-loop-helix proteins , 1990, Cell.

[44]  S. Carroll,et al.  Hairy and Emc negatively regulate morphogenetic furrow progression in the drosophila eye , 1995, Cell.

[45]  G. Campbell,et al.  Transducing the Dpp Morphogen Gradient in the Wing of Drosophila Regulation of Dpp Targets by brinker , 1999, Cell.

[46]  N. Baker,et al.  Drosophila eye development: Notch and Delta amplify a neurogenic pattern conferred on the morphogenetic furrow by scabrous , 1995, Mechanisms of Development.

[47]  J. Modolell,et al.  The extramacrochaetae gene provides information for sensory organ patterning. , 1992, The EMBO journal.

[48]  G M Rubin,et al.  Spacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous. , 1990, Science.

[49]  D. Yamamoto,et al.  The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. , 1997, Development.

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

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

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

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

[54]  J. Posakony,et al.  The Drosophila extramacrochaetae protein antagonizes sequence-specific DNA binding by daughterless/achaete-scute protein complexes. , 1991, Development.

[55]  P. A. Powell,et al.  Spatial regulation of proneural gene activity: auto- and cross-activation of achaete is antagonized by extramacrochaetae. , 1992, Genes & development.

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

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

[58]  J. Langeland,et al.  Three-color immunofluorescence imaging of Drosophila embryos by laser scanning confocal microscopy. , 1993, BioTechniques.