Quantifying the Gurken morphogen gradient in Drosophila oogenesis.

Quantitative information about the distribution of morphogens is crucial for understanding their effects on cell-fate determination, yet it is difficult to obtain through direct measurements. We have developed a parameter estimation approach for quantifying the spatial distribution of Gurken, a TGFalpha-like EGFR ligand that acts as a morphogen in Drosophila oogenesis. Modeling of Gurken/EGFR system shows that the shape of the Gurken gradient is controlled by a single dimensionless parameter, the Thiele modulus, which reflects the relative importance of ligand diffusion and degradation. By combining the model with genetic alterations of EGFR levels, we have estimated the value of the Thiele modulus in the wild-type egg chamber. This provides a direct characterization of the shape of the Gurken gradient and demonstrates how parameter estimation techniques can be used to quantify morphogen gradients in development.

[1]  C. Berg The Drosophila shell game: patterning genes and morphological change. , 2005, Trends in genetics : TIG.

[2]  T. Schüpbach,et al.  The Drosophila TGF-α-like protein Gurken: expression and cellular localization during Drosophila oogenesis , 1996, Mechanisms of Development.

[3]  L. Riddiford,et al.  Border of Notch activity establishes a boundary between the two dorsal appendage tube cell types. , 2006, Developmental biology.

[4]  T. Rebello,et al.  Capicua regulates follicle cell fate in the Drosophila ovary through repression of mirror , 2006, Development.

[5]  T. Schüpbach,et al.  The relationship between ovarian and embryonic dorsoventral patterning in Drosophila. , 1994, Development.

[6]  S. Shvartsman,et al.  Discrete models of autocrine cell communication in epithelial layers. , 2003, Biophysical journal.

[7]  Integration of epithelial patterning and morphogenesis in Drosophila ovarian follicle cells , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[8]  Qing Nie,et al.  Formation of the BMP activity gradient in the Drosophila embryo. , 2005, Developmental cell.

[9]  W. Bialek,et al.  Diffusion and scaling during early embryonic pattern formation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Gurdon,et al.  Morphogen gradient interpretation , 2001, Nature.

[11]  Douglas A Lauffenburger,et al.  Modeling and computational analysis of EGF receptor-mediated cell communication in Drosophila oogenesis. , 2002, Development.

[12]  T. Lecuit,et al.  Dpp receptor levels contribute to shaping the Dpp morphogen gradient in the Drosophila wing imaginal disc. , 1998, Development.

[13]  Stanislav Y Shvartsman,et al.  Computational analysis of EGFR inhibition by Argos. , 2005, Developmental biology.

[14]  S. Shvartsman,et al.  Ligand trapping in epithelial layers and cell cultures. , 2004, Biophysical chemistry.

[15]  M. Freeman,et al.  An Autoregulatory Cascade of EGF Receptor Signaling Patterns the Drosophila Egg , 1998, Cell.

[16]  Larry Wasserman,et al.  All of Statistics: A Concise Course in Statistical Inference , 2004 .

[17]  Alfonso Martinez Arias,et al.  Molecular Principles of Animal Development , 2002 .

[18]  T. Schüpbach,et al.  The drosophila dorsoventral patterning gene gurken produces a dorsally localized RNA and encodes a TGFα-like protein , 1993, Cell.

[19]  A. Teleman,et al.  Shaping Morphogen Gradients , 2001, Cell.

[20]  R. Steward,et al.  Requirement for phosphorylation and localization of the Bicaudal-D protein in Drosophila oocyte differentiation , 1991, Cell.

[21]  Stanislav Y Shvartsman,et al.  Quantitative analysis of the GAL4/UAS system in Drosophila oogenesis , 2006, Genesis.

[22]  T. Schupbach,et al.  Dorsoventral axis formation in Drosophila depends on the correct dosage of the gene gurken. , 1994, Development.

[23]  D. Poccia Molecular Principles of Animal Development.ByAlfonso Martinez Ariasand, Alison Stewart.Oxford and New York: Oxford University Press.£28.99 (paper). xiii + 410 p; ill.; index. ISBN: 0–19–879284–0. 2002. , 2003 .

[24]  A. Michelson,et al.  Signalling by the Drosophila epidermal growth factor receptor is required for the specification and diversification of embryonic muscle progenitors. , 1998, Development.

[25]  S. Roth,et al.  Local Gurken signaling and dynamic MAPK activation during Drosophila oogenesis , 1999, Mechanisms of Development.

[26]  T. Schüpbach,et al.  EGF receptor signaling in Drosophila oogenesis. , 1999, Current topics in developmental biology.

[27]  B. Shilo,et al.  Signaling by the Drosophila epidermal growth factor receptor pathway during development. , 2003, Experimental cell research.

[28]  H. Ruohola-Baker,et al.  Genome wide analysis of transcript levels after perturbation of the EGFR pathway in the Drosophila ovary , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[29]  V. S. Vaidhyanathan,et al.  Transport phenomena , 2005, Experientia.

[30]  M. Scott,et al.  Incredible journey: how do developmental signals travel through tissue? , 2004, Genes & development.

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

[32]  R. Kelley,et al.  Specific isoforms of squid, a Drosophila hnRNP, perform distinct roles in Gurken localization during oogenesis. , 1999, Genes & development.

[33]  N. Perrimon,et al.  The Transmembrane Molecule Kekkon 1 Acts in a Feedback Loop to Negatively Regulate the Activity of the Drosophila EGF Receptor during Oogenesis , 1999, Cell.

[34]  T. Schüpbach,et al.  The Drosophila TGF-alpha-like protein Gurken: expression and cellular localization during Drosophila oogenesis. , 1996, Mechanisms of development.

[35]  S. Shvartsman,et al.  Systems-level questions in Drosophila oogenesis. , 2005, Systems biology.

[36]  T. Schüpbach Germ line and soma cooperate during oogenesis to establish the dorsoventral pattern of egg shell and embryo in Drosophila melanogaster , 1987, Cell.

[37]  H. Steven Wiley,et al.  A steady state model for analyzing the cellular binding, internalization and degradation of polypeptide ligands , 1981, Cell.

[38]  Diffusion and chemical transformation. , 1973, Science.

[39]  S. Roth The origin of dorsoventral polarity in Drosophila. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[40]  W. Saltzman Tissue Engineering: Engineering Principles for the Design of Replacement Organs and Tissues , 2004 .

[41]  N. Barkai,et al.  Robustness of the BMP morphogen gradient in Drosophila embryonic patterning , 2022 .

[42]  William McGinnis,et al.  Multiplex Detection of RNA Expression in Drosophila Embryos , 2004, Science.

[43]  J. S. Britton,et al.  Pointed, an ETS domain transcription factor, negatively regulates the EGF receptor pathway in Drosophila oogenesis. , 1996, Development.

[44]  G. Struhl,et al.  The torso receptor localizes as well as transduces the spatial signal specifying terminal body pattern in Drosophila , 1993, Nature.

[45]  Osamu Shimmi,et al.  Facilitated Transport of a Dpp/Scw Heterodimer by Sog/Tsg Leads to Robust Patterning of the Drosophila Blastoderm Embryo , 2005, Cell.

[46]  C. Berg,et al.  Mosaic analyses reveal the function of Drosophila Ras in embryonic dorsoventral patterning and dorsal follicle cell morphogenesis. , 2002, Development.

[47]  N. Perrimon,et al.  Raf acts downstream of the EGF receptor to determine dorsoventral polarity during Drosophila oogenesis. , 1994, Genes & development.

[48]  David H. Sharp,et al.  Dynamic control of positional information in the early Drosophila embryo , 2004, Nature.

[49]  V. Cavaliere,et al.  Specific domains drive VM32E protein distribution and integration in Drosophila eggshell layers. , 2001, Journal of cell science.

[50]  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.

[51]  Qing Nie,et al.  Do morphogen gradients arise by diffusion? , 2002, Developmental cell.

[52]  B. Shilo,et al.  Sequential activation of the EGF receptor pathway during Drosophila oogenesis establishes the dorsoventral axis. , 1998, Development.

[53]  Stephen S. Gisselbrecht,et al.  New fluorescent protein reporters for use with the drosophila gal4 expression system and for vital detection of balancer chromosomes , 2002, Genesis.

[54]  D. Stein,et al.  Dorsoventral Patterning: A Direct Route from Ovary to Embryo , 2002, Current Biology.

[55]  D. Tautz,et al.  A non-radioactive in situ hybridization method for the localization of specific RNAs in Drosophila embryos reveals translational control of the segmentation gene hunchback , 1989, Chromosoma.

[56]  L. Dobens,et al.  Drosophila bunched integrates opposing DPP and EGF signals to set the operculum boundary. , 2000, Development.

[57]  L. Griffith,et al.  Capturing complex 3D tissue physiology in vitro , 2006, Nature Reviews Molecular Cell Biology.

[58]  Marcos González-Gaitán,et al.  Signal dispersal and transduction through the endocytic pathway , 2003, Nature Reviews Molecular Cell Biology.

[59]  S. Roth,et al.  Mechanisms of Gurken-dependent pipe regulation and the robustness of dorsoventral patterning in Drosophila. , 2002, Development.

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

[61]  S. Roth,et al.  Combined activities of Gurken and decapentaplegic specify dorsal chorion structures of the Drosophila egg. , 2000, Development.

[62]  Stanislav Y. Shvartsman,et al.  Argos inhibits epidermal growth factor receptor signalling by ligand sequestration , 2004, Nature.

[63]  Tetsuya Tabata,et al.  Morphogens, their identification and regulation , 2004, Development.

[64]  M. Freeman Feedback control of intercellular signalling in development , 2000, Nature.

[65]  N. Perrimon,et al.  Mechanism of activation of the Drosophila EGF Receptor by the TGFalpha ligand Gurken during oogenesis. , 2002, Development.

[66]  Naama Barkai,et al.  Self-enhanced ligand degradation underlies robustness of morphogen gradients. , 2003, Developmental cell.

[67]  L. Dobens,et al.  Bunched sets a boundary for Notch signaling to pattern anterior eggshell structures during Drosophila oogenesis. , 2005, Developmental biology.

[68]  P. Pantazis,et al.  Dpp gradient formation by dynamin-dependent endocytosis: receptor trafficking and the diffusion model , 2004, Development.

[69]  S. T. Buckland,et al.  An Introduction to the Bootstrap. , 1994 .

[70]  R. King Ovarian Development in Drosophila Melanogaster , 1970 .

[71]  Eric F. Wieschaus,et al.  folded gastrulation, cell shape change and the control of myosin localization , 2005, Development.

[72]  T. Schüpbach,et al.  Localized Requirements for windbeutel and pipe Reveal a Dorsoventral Prepattern within the Follicular Epithelium of the Drosophila Ovary , 1998, Cell.

[73]  B. Shilo,et al.  Secreted Spitz triggers the DER signaling pathway and is a limiting component in embryonic ventral ectoderm determination. , 1995, Genes & development.

[74]  L. Stevens,et al.  Spatially Restricted Expression of pipe in the Drosophila Egg Chamber Defines Embryonic Dorsal–Ventral Polarity , 1998, Cell.

[75]  Xinhua Lin,et al.  Drosophila Dpp Morphogen Movement Is Independent of Dynamin-Mediated Endocytosis but Regulated by the Glypican Members of Heparan Sulfate Proteoglycans , 2004, Cell.

[76]  T. Schüpbach,et al.  D-cbl, a Negative Regulator of the Egfr Pathway, Is Required for Dorsoventral Patterning in Drosophila Oogenesis , 2000, Cell.

[77]  Allan C. Spradling Developmental Genetics of oogenesis , 1993 .