A Model of the Spatio-temporal Dynamics of Drosophila Eye Disc Development

Patterning and growth are linked during early development and have to be tightly controlled to result in a functional tissue or organ. During the development of the Drosophila eye, this linkage is particularly clear: the growth of the eye primordium mainly results from proliferating cells ahead of the morphogenetic furrow (MF), a moving signaling wave that sweeps across the tissue from the posterior to the anterior side, that induces proliferating cells anterior to it to differentiate and become cell cycle quiescent in its wake. Therefore, final eye disc size depends on the proliferation rate of undifferentiated cells and on the speed with which the MF sweeps across the eye disc. We developed a spatio-temporal model of the growing eye disc based on the regulatory interactions controlled by the signals Decapentaplegic (Dpp), Hedgehog (Hh) and the transcription factor Homothorax (Hth) and explored how the signaling patterns affect the movement of the MF and impact on eye disc growth. We used published and new quantitative data to parameterize the model. In particular, two crucial parameter values, the degradation rate of Hth and the diffusion coefficient of Hh, were measured. The model is able to reproduce the linear movement of the MF and the termination of growth of the primordium. We further show that the model can explain several mutant phenotypes, but fails to reproduce the previously observed scaling of the Dpp gradient in the anterior compartment.

[1]  R. Tibshirani,et al.  Generalized Additive Models , 1986 .

[2]  Suzanne Eaton,et al.  Lipoprotein particles are required for Hedgehog and Wingless signalling , 2005, Nature.

[3]  Daniel Aguilar-Hidalgo,et al.  A Hh-driven gene network controls specification, pattern and size of the Drosophila simple eyes , 2013, Development.

[4]  Takuya Akiyama,et al.  Decapentaplegic and growth control in the developing Drosophila wing , 2015, Nature.

[5]  F. Hoffmann,et al.  Pattern-specific expression of the Drosophila decapentaplegic gene in imaginal disks is regulated by 3' cis-regulatory elements. , 1990, Genes & development.

[6]  N. Baker,et al.  Retinal determination genes as targets and possible effectors of extracellular signals. , 2009, Developmental biology.

[7]  Siddhartha Mishra,et al.  Scaling morphogen gradients during tissue growth by a cell division rule , 2014, Development.

[8]  Steven Russell,et al.  The Flannotator - a gene and protein expression annotation tool for Drosophila melanogaster , 2009, Bioinform..

[9]  Seymour Benzer,et al.  The eyes absent gene: Genetic control of cell survival and differentiation in the developing Drosophila eye , 1993, Cell.

[10]  G Forgacs.  Surface tension and viscoelastic properties of embryonic tissues depend on the cytoskeleton. , 1998, The Biological bulletin.

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

[12]  Y. Kalaidzidis,et al.  Kinetics of Morphogen Gradient Formation , 2007, Science.

[13]  Luis M. Escudero,et al.  Myosin II regulates complex cellular arrangement and epithelial architecture in Drosophila. , 2007, Developmental cell.

[14]  Isabel Guerrero,et al.  Patched, the receptor of Hedgehog, is a lipoprotein receptor , 2008, Proceedings of the National Academy of Sciences.

[15]  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.

[16]  A. Bhattacharya,et al.  Cell cycle arrest by a gradient of Dpp signaling during Drosophila eye development , 2010, BMC Developmental Biology.

[17]  Matthew Slattery,et al.  Transcription factor choice in the Hippo signaling pathway: homothorax and yorkie regulation of the microRNA bantam in the progenitor domain of the Drosophila eye imaginal disc. , 2009, Genes & development.

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

[19]  S. Bergmann,et al.  Dpp Signaling Activity Requires Pentagone to Scale with Tissue Size in the Growing Drosophila Wing Imaginal Disc , 2011, PLoS biology.

[20]  Frank Jülicher,et al.  Investigating the principles of morphogen gradient formation: from tissues to cells. , 2012, Current opinion in genetics & development.

[21]  Steinberg,et al.  Liquid properties of embryonic tissues: Measurement of interfacial tensions. , 1994, Physical review letters.

[22]  Richard S. Mann,et al.  Control of antennal versus leg development in Drosophila , 1998, Nature.

[23]  Marcos Nahmad,et al.  Dynamic Interpretation of Hedgehog Signaling in the Drosophila Wing Disc , 2009, PLoS biology.

[24]  Ginés Morata,et al.  Compartments and the control of growth in the Drosophila wing imaginal disc , 2006, Development.

[25]  Sean B. Carroll,et al.  Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene , 1996, Nature.

[26]  Frank Jülicher,et al.  Growth control by a moving morphogen gradient during Drosophila eye development , 2014, Development.

[27]  Franck Pichaud,et al.  homothorax and iroquois-C genes are required for the establishment of territories within the developing eye disc , 2000, Mechanisms of Development.

[28]  Fernando Casares,et al.  hth maintains the pool of eye progenitors and its downregulation by Dpp and Hh couples retinal fate acquisition with cell cycle exit. , 2010, Developmental biology.

[29]  Fisun Hamaratoglu,et al.  Dpp spreading is required for medial but not for lateral wing disc growth , 2015, Nature.

[30]  Dagmar Iber,et al.  A quantitative analysis of growth control in the Drosophila eye disc , 2016, Development.

[31]  Nathan T Mortimer,et al.  Pointed regulates an eye-specific transcriptional enhancer in the Drosophila hedgehog gene, which is required for the movement of the morphogenetic furrow , 2005, Development.

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

[33]  Hyung Don Ryoo,et al.  Nuclear Translocation of Extradenticle Requires homothorax , which Encodes an Extradenticle-Related Homeodomain Protein , 1997, Cell.

[34]  Dagmar Iber,et al.  Dynamic scaling of morphogen gradients on growing domains , 2014, Nature Communications.

[35]  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.

[36]  Uri Alon,et al.  Using bleach-chase to measure protein half-lives in living cells , 2012, Nature Protocols.

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

[38]  Emmanuele DiBenedetto,et al.  Simplified Equation to Extract Diffusion Coefficients from Confocal FRAP Data , 2012, Traffic.

[39]  Franck Pichaud,et al.  Combinatorial control of Drosophila eye development by eyeless, homothorax, and teashirt. , 2002, Genes & development.

[40]  N. Baker,et al.  Patterning signals and proliferation in Drosophila imaginal discs. , 2007, Current opinion in genetics & development.

[41]  Rhian F. Walther,et al.  Hedgehog signaling is a principal inducer of Myosin-II-driven cell ingression in Drosophila epithelia. , 2007, Developmental cell.

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

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

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

[45]  S. Selleck,et al.  Regulation of Cell Cycle Synchronization by decapentaplegic During Drosophila Eye Development , 1997, Science.

[46]  Fernando Casares,et al.  Size matters: the contribution of cell proliferation to the progression of the specification Drosophila eye gene regulatory network. , 2010, Developmental biology.

[47]  D. Kalderon,et al.  Regulation of cell proliferation and patterning in Drosophila oogenesis by Hedgehog signaling. , 2000, Development.

[48]  Frank Jülicher,et al.  Response to Comment on “Dynamics of Dpp Signaling and Proliferation Control” , 2012, Science.

[49]  J. Horsfield,et al.  decapentaplegic is required for arrest in G1 phase during Drosophila eye development. , 1998, Development.

[50]  Robert Dillon,et al.  Short- and long-range effects of Sonic hedgehog in limb development , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Enrico Gratton,et al.  Free Extracellular Diffusion Creates the Dpp Morphogen Gradient of the Drosophila Wing Disc , 2012, Current Biology.

[52]  Frank Jülicher,et al.  Dynamics of anisotropic tissue growth , 2008 .

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

[54]  T. J. Jaw,et al.  The Homothorax homeoprotein activates the nuclear localization of another homeoprotein, extradenticle, and suppresses eye development in Drosophila. , 1998, Genes & development.

[55]  Ginés Morata,et al.  Cells compete for Decapentaplegic survival factor to prevent apoptosis in Drosophila wing development , 2002, Nature.

[56]  Christian Dahmann,et al.  Hedgehog and Dpp signaling induce cadherin Cad86C expression in the morphogenetic furrow during Drosophila eye development , 2008, Mechanisms of Development.

[57]  Uri Alon,et al.  Proteome Half-Life Dynamics in Living Human Cells , 2011, Science.

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

[59]  A. Kicheva,et al.  Dynamics of Dpp Signaling and Proliferation Control , 2011, Science.

[60]  Isabel Guerrero,et al.  Patched controls the Hedgehog gradient by endocytosis in a dynamin-dependent manner, but this internalization does not play a major role in signal transduction , 2004, Development.