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The wing and the eye: a parsimonious theory for scaling and growth control?

Advanced Review

Marcos Gonzalez‐Gaitan, Frank Jülicher, Daniel Aguilar‐Hidalgo, Maria Romanova‐Michaelides

Published Online: Jun 24 2015

DOI: 10.1002/wdev.195

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How a developing organ grows and patterns to its final shape is an important question in developmental biology. Studies of growth and patterning in the Drosophila wing imaginal disc have identified a key player, the morphogen Decapentaplegic (Dpp). These studies provided insights into our understanding of growth control and scaling: expansion of the Dpp gradient correlated with the growth of the tissue. A recent report on growth of a Drosophila organ other than the wing, the eye imaginal disc, prompts a reconsideration of our models of growth control. Despite striking differences between the two, the Dpp gradient scales with the target tissues of both organs and the growth of both the wing and the eye is controlled by Dpp. The goal of this review is to discuss whether a parsimonious model of scaling and growth control can explain the relationship between the Dpp gradient and growth in these two different developmental systems. WIREs Dev Biol 2015, 4:591–608. doi: 10.1002/wdev.195 This article is categorized under: Establishment of Spatial and Temporal Patterns > Gradients Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing

Wing versus Eye. SEM images of the entire fly (a), the wing (b), and the eye (c). Confocal microscopy images of the wing (d, green signal is the fluorescently labeled Decapentaplegic (Dpp), the wing disc is outlined by the white punctuate line) and eye (e, the red signal is an antibody staining of Hairy, the target gene of Dpp, the eye disc is outline by the white punctuate line) discs with corresponding Dpp spatial profiles (f and g). Letters A and P indicate the anterior and the posterior compartments, respectively. The red arrow in (g) represents the direction of the movement of the furrow.

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The temporal growth rule. (a and b) Relative temporal differences () can explain the uniform spatial proliferation profile in the wing disc and the spatial profile of proliferation in the eye. (c and d) General temporal growth rule expressions for and the growth rate (g). From these general expressions, the specific cases of the wing (e) and the eye (f) can be derived. (c) This general equation accounts for all the inputs into (relative changes of Dpp in time) both in the wing and the eye: (i) The change of the amplitude C_max with time (); (ii) Changes due to the movement of cells relative to the Dpp source (and therefore relative to the Dpp gradient) with the velocity v_cell. There are two components of this movement: the movement of the source with the velocity v_s and the movement due to the proliferation of cells with the velocity v_g; (iii) Because of the gradient scaling with L_a, the term captures the change (increase or decrease) in the signaling levels of a cell, when L_a expands or shrinks, which is accompanied by an expansion or shrinkage of the gradient. (e) The temporal growth rule expression for the case of a system with a nonmoving Dpp source (v_s = 0) and homogeneous growth. Therefore, (Drosophila wing disc). (f) The temporal growth rule expression for the case in which the source moves (v_s ≠ 0) and the target tissue length (L_a) and the gradient amplitude (C_max) are constant in time. The sole cause of increase of cellular Dpp concentration is therefore the movement of cells upward the gradient due to the movement of the furrow (Drosophila eye disc during the developmental time between 65 and 85 h after hatching).

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Growth rules. (a) Absolute concentration model: the absolute concentration is not homogeneous in space thus cannot yield homogeneous growth. (b) In combination with the effect of the mechanical stress on growth, the absolute concentration model can explain homogeneous growth. (c) Spatial differences model. Spatial differences are not homogeneous in space and cannot explain homogeneous growth. (d) Relative spatial differences are spatially uniform and can explain homogeneous growth.

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Scaling mechanisms. (a) Expansion–repression mechanism. (b) Expansion–dilution mechanism. (c) Two opposing gradients. (d) In the case of the advection–dilution scaling mechanism, the spread of the morphogen in the target tissue is described by the kinetic parameters of morphogen transport: the diffusion and the degradation of the morphogen and by two phenomena related to the growth of the tissue: advection and dilution.

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Decapentaplegic (Dpp) gradient and proliferation profiles. (a) Dpp is secreted from a distinct source in the center of a wing disc (in red) and spreads in the target tissue to form a gradient of concentration. (b) The Dpp concentration profile in the target tissue of the growing wing disc increases in width and in amplitude from t₁ to t₂. (c) The proliferation rate in the wing disc is roughly homogeneous in the entire target tissue. (d) In the eye disc Dpp is transcribed at the morphogenetic furrow (in red) that separate the differentiating ommatidia from the anterior undifferentiated cells (on the right of the Dpp source). (e) The furrow sweeps across the tissue from anterior to posterior. This results in a moving Dpp gradient from t₁ to t₂. (f) As the Dpp gradient starts moving, growth in the anterior target cells becomes strongly position‐dependent: there is a peak of proliferation in front of the furrow. Anterior to this peak the growth rate decays.

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References

Aristotle. Metaphysics. 1st century CE.
Driesch, H. The Science and Philosophy of the Organism. In: The Gifford Lectures Delivered Before the University of Aberdeen in the Year 1907–1908. Aberdeen: printed for the University, 1908–09.
Baena‐Lopez, LA, Nojima, H, Vincent, JP. Integration of morphogen signalling within the growth regulatory network. Curr Opin Cell Biol 2012, 24:166–172.
Dekanty, A, Milan, M. The interplay between morphogens and tissue growth. EMBO Rep 2011, 12:1003–1010.
Restrepo, S, Zartman, JJ, Basler, K. Coordination of patterning and growth by the morphogen DPP. Curr Biol 2014, 24:R245–R255.
Wartlick, O, Gonzalez‐Gaitan, M. The missing link: implementation of morphogenetic growth control on the cellular and molecular level. Curr Opin Genet Dev 2011, 21:690–695.
Wartlick, O, Mumcu, P, Julicher, F, Gonzalez‐Gaitan, M. Understanding morphogenetic growth control—lessons from flies. Nat Rev Mol Cell Biol 2011, 12:594–604.
Umulis, DM, Othmer, HG. Mechanisms of scaling in pattern formation. Development 2013, 140:4830–4843.
Lecuit, T, Le Goff, L. Orchestrating size and shape during morphogenesis. Nature 2007, 450:189–192.
Schwank, G, Basler, K. Regulation of organ growth by morphogen gradients. Cold Spring Harb Perspect Biol 2010, 2:a001669.
Wolpert, L. Positional information and the spatial pattern of cellular differentiation. J Theor Biol 1969, 25:1–47.
Bollenbach, T, Pantazis, P, Kicheva, A, Bokel, C, Gonzalez‐Gaitan, M, Julicher, F. Precision of the Dpp gradient. Development 2008, 135:1137–1146.
Entchev, EV, Schwabedissen, A, Gonzalez‐Gaitan, M. Gradient formation of the TGF‐β homolog Dpp. Cell 2000, 103:981–991.
Kim, J, Johnson, K, Chen, HJ, Carroll, S, Laughon, A. Drosophila mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic. Nature 1997, 388:304–308.
Lecuit, T, Brook, WJ, Ng, M, Calleja, M, Sun, H, Cohen, SM. Two distinct mechanisms for long‐range patterning by Decapentaplegic in the Drosophila wing. Nature 1996, 381:387–393.
Nellen, D, Burke, R, Struhl, G, Basler, K. Direct and long‐range action of a DPP morphogen gradient. Cell 1996, 85:357–368.
Teleman, AA, Cohen, SM. Dpp gradient formation in the Drosophila wing imaginal disc. Cell 2000, 103:971–980.
Day, SJ, Lawrence, PA. Measuring dimensions: the regulation of size and shape. Development 2000, 127:2977–2987.
Rogulja, D, Irvine, KD. Regulation of cell proliferation by a morphogen gradient. Cell 2005, 123:449–461.
Wartlick, O, Mumcu, P, Kicheva, A, Bittig, T, Seum, C, Julicher, F, Gonzalez‐Gaitan, M. Dynamics of Dpp signaling and proliferation control. Science 2011, 331:1154–1159.
Aegerter‐Wilmsen, T, Aegerter, CM, Hafen, E, Basler, K. Model for the regulation of size in the wing imaginal disc of Drosophila. Mech Dev 2007, 124:318–326.
Hufnagel, L, Teleman, AA, Rouault, H, Cohen, SM, Shraiman, BI. On the mechanism of wing size determination in fly development. Proc Natl Acad Sci USA 2007, 104:3835–3840.
Shraiman, BI. Mechanical feedback as a possible regulator of tissue growth. Proc Natl Acad Sci USA 2005, 102:3318–3323.
Affolter, M, Basler, K. The Decapentaplegic morphogen gradient: from pattern formation to growth regulation. Nat Rev Genet 2007, 8:663–674.
Wartlick, O, Kicheva, A, Gonzalez‐Gaitan, M. Morphogen gradient formation. Cold Spring Harb Perspect Biol 2009, 1:a001255.
Wartlick, O, Julicher, F, Gonzalez‐Gaitan, M. Growth control by a moving morphogen gradient during Drosophila eye development. Development 2014, 141:1884–1893.
Garcia‐Bellido, A, Merriam, JR. Parameters of the wing imaginal disc development of Drosophila melanogaster. Dev Biol 1971, 24:61–87.
Cohen, SM. Imaginal disc development. In: Bate, M, Martinez Arias, A, eds. The Development of Drosophila Melanogaster, vol. 2. New York, NY: Cold Spring Harbor Lab; 1993, 747–843.
Couso, JP, Gonzalez‐Gaitan, M. Embryonic limb development in Drosophila. Trends Genet 1993, 9:371–373.
Fristrom, D, Fristrom, JW. The metamorphic development of the adult epidermis. In: Bate, M, Martinez Arias, A, eds. The Development of Drosophila Melanogaster, vol. 2. Cold Spring Harbor Laboratory Press; 1993, 843–899.
Cohen, SM. Imaginal disc development. In: Bate, M, Martinez Arias, A, eds. The Development of Drosophila Melanogaster. New York, NY: Cold Spring Harbor Lab; 1993, 747–843.
Schubiger, M, Palka, J. Changing spatial patterns of DNA replication in the developing wing of Drosophila. Dev Biol 1987, 123:145–153.
Alberts, B, Johnson, A, Lewis, J, Raff, M, Robert, K, Walter, P. Molecular Biology of the Cell Extended Edition. New York, NY: Garland Science; 2008.
Wolff, T, Ready, DF. Pattern formation in the Drosophila retina. In: Bate, M, Martinez Arias, A, eds. The Development of Drosophila Melanogaster, vol. 2. New York, NY: Cold Spring Harbor Lab; 1993, 1277–1327.
Wieschaus, E, Gehring, W. Clonal analysis of primordial disc cells in the early embryo of Drosophila melanogaster. Dev Biol 1976, 50:249–263.
Cagan, R. Principles of Drosophila eye differentiation. Curr Top Dev Biol 2009, 89:115–135.
Baker, NE. Cell proliferation, survival, and death in the Drosophila eye. Semin Cell Dev Biol 2001, 12:499–507.
Tomlinson, A. The cellular dynamics of pattern formation in the eye of Drosophila. J Embryol Exp Morphol 1985, 89:313–331.
Burke, R, Basler, K. Hedgehog‐dependent patterning in the Drosophila eye can occur in the absence of Dpp signaling. Dev Biol 1996, 179:360–368.
Penton, A, Selleck, SB, Hoffmann, FM. Regulation of cell cycle synchronization by Decapentaplegic during Drosophila eye development. Science 1997, 275:203–206.
Horsfield, J, Penton, A, Secombe, J, Hoffman, FM, Richardson, H. Decapentaplegic is required for arrest in G1 phase during Drosophila eye development. Development 1998, 125:5069–5078.
Firth, LC, Bhattacharya, A, Baker, NE. Cell cycle arrest by a gradient of Dpp signaling during Drosophila eye development. BMC Dev Biol 2010, 10:28.
Morata, G, Lawrence, PA. The development of wingless, a homeotic mutation of Drosophila. Dev Biol 1977, 56:227–240.
Basler, K, Struhl, G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 1994, 368:208–214.
Zecca, M, Basler, K, Struhl, G. Sequential organizing activities of engrailed, hedgehog and Decapentaplegic in the Drosophila wing. Development 1995, 121:2265–2278.
Couso, JP, Knust, E, Martinez, AA. Serrate and wingless cooperate to induce vestigial gene expression and wing formation in Drosophila. Curr Biol 1995, 5:1437–1448.
ten Dijke, P, Miyazono, K, Heldin, CH. Signaling via hetero‐oligomeric complexes of type I and type II serine/threonine kinase receptors. Curr Opin Cell Biol 1996, 8:139–145.
Ruberte, E, Marty, T, Nellen, D, Affolter, M, Basler, K. An absolute requirement for both the type II and type I receptors, punt and thick veins, for dpp signaling in vivo. Cell 1995, 80:889–897.
Rushlow, C, Colosimo, PF, Lin, MC, Xu, M, Kirov, N. Transcriptional regulation of the Drosophila gene zen by competing Smad and Brinker inputs. Genes Dev 2001, 15:340–351.
Weiss, A, Charbonnier, E, Ellertsdottir, E, Tsirigos, A, Wolf, C, Schuh, R, Pyrowolakis, G, Affolter, M. A conserved activation element in BMP signaling during Drosophila development. Nat Struct Mol Biol 2010, 17:69–76.
Kirkpatrick, H, Johnson, K, Laughon, A. Repression of dpp targets by binding of Brinker to mad sites. J Biol Chem 2001, 276:18216–18222.
Moser, M, Campbell, G. Generating and interpreting the Brinker gradient in the Drosophila wing. Dev Biol 2005, 286:647–658.
Campbell, G, Tomlinson, A. Transducing the Dpp morphogen gradient in the wing of Drosophila: regulation of Dpp targets by Brinker. Cell 1999, 96:553–562.
Jazwinska, A, Kirov, N, Wieschaus, E, Roth, S, Rushlow, C. The Drosophila gene Brinker reveals a novel mechanism of Dpp target gene regulation. Cell 1999, 96:563–573.
Minami, M, Kinoshita, N, Kamoshida, Y, Tanimoto, H, Tabata, T. Brinker is a target of Dpp in Drosophila that negatively regulates Dpp‐dependent genes. Nature 1999, 398:242–246.
Kamiya, Y, Miyazono, K, Miyazawa, K. Specificity of the inhibitory effects of Dad on TGF‐β family type I receptors, Thickveins, Saxophone, and Baboon in Drosophila. FEBS Lett 2008, 582:2496–2500.
de Celis, JF, Barrio, R, Kafatos, FC. A gene complex acting downstream of dpp in Drosophila wing morphogenesis. Nature 1996, 381:421–424.
Sivasankaran, R, Vigano, MA, Muller, B, Affolter, M, Basler, K. Direct transcriptional control of the Dpp target omb by the DNA binding protein Brinker. EMBO J 2000, 19:6162–6172.
Brown, NL, Sattler, CA, Markey, DR, Carroll, SB. Hairy gene function in the Drosophila eye: normal expression is dispensable but ectopic expression alters cell fates. Development 1991, 113:1245–1256.
Tanimoto, H, Itoh, S, ten Dijke, P, Tabata, T. Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs. Mol Cell 2000, 5:59–71.
Kicheva, A, Pantazis, P, Bollenbach, T, Kalaidzidis, Y, Bittig, T, Julicher, F, Gonzalez‐Gaitan, M. Kinetics of morphogen gradient formation. Science 2007, 315:521–525.
Hecht, PM, Anderson, KV. Extracellular proteases and embryonic pattern formation. Trends Cell Biol 1992, 2:197–202.
Kicheva, A, Bollenbach, T, Wartlick, O, Julicher, F, Gonzalez‐Gaitan, M. Investigating the principles of morphogen gradient formation: from tissues to cells. Curr Opin Genet Dev 2012, 22:527–532.
Zhou, S, Lo, WC, Suhalim, JL, Digman, MA, Gratton, E, Nie, Q, Lander, AD. Free extracellular diffusion creates the Dpp morphogen gradient of the Drosophila wing disc. Curr Biol 2012, 22:668–675.
Kojima, T, Michiue, T, Orihara, M, Saigo, K. Induction of a mirror‐image duplication of anterior wing structures by localized hedgehog expression in the anterior compartment of Drosophila melanogaster wing imaginal discs. Gene 1994, 148:211–217.
Tabata, T, Kornberg, TB. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 1994, 76:89–102.
Heberlein, U, Wolff, T, Rubin, GM. The TGF β homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina. Cell 1993, 75:913–926.
Heberlein, U, Singh, CM, Luk, AY, Donohoe, TJ. Growth and differentiation in the Drosophila eye coordinated by hedgehog. Nature 1995, 373:709–711.
Dominguez, M. Dual role for Hedgehog in the regulation of the proneural gene atonal during ommatidia development. Development 1999, 126:2345–2353.
Ma, C, Zhou, Y, Beachy, PA, Moses, K. The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye. Cell 1993, 75:927–938.
Strutt, DI, Mlodzik, M. Hedgehog is an indirect regulator of morphogenetic furrow progression in the Drosophila eye disc. Development 1997, 124:3233–3240.
Greenwood, S, Struhl, G. Progression of the morphogenetic furrow in the Drosophila eye: the roles of Hedgehog, Decapentaplegic and the Raf pathway. Development 1999, 126:5795–5808.
Curtiss, J, Mlodzik, M. Morphogenetic furrow initiation and progression during eye development in Drosophila: the roles of Decapentaplegic, hedgehog and eyes absent. Development 2000, 127:1325–1336.
Schwank, G, Restrepo, S, Basler, K. Growth regulation by Dpp: an essential role for Brinker and a non‐essential role for graded signaling levels. Development 2008, 135:4003–4013.
Baena‐Lopez, LA, Baonza, A, Garcia‐Bellido, A. The orientation of cell divisions determines the shape pf Drosophila organs. Curr Biol 2005, 15:1640–1644.
Lecuit, T, Cohen, SM. Dpp receptor levels contribute to shaping the Dpp morphogen gradient in the Drosophila wing imaginal disc. Development 1998, 125:4901–4907.
Ben‐Zvi, D, Shilo, BZ, Barkai, N. Scaling of morphogen gradients. Curr Opin Genet Dev 2011, 21:704–710.
Hamaratoglu, F, de Lachapelle, AM, Pyrowolakis, G, Bergmann, S, Affolter, M. Dpp signaling activity requires Pentagone to scale with tissue size in the growing Drosophila wing imaginal disc. PLoS Biol 2011, 9:e1001182.
Ben‐Zvi, D, Pyrowolakis, G, Barkai, N, Shilo, BZ. Expansion‐repression mechanism for scaling the Dpp activation gradient in Drosophila wing imaginal discs. Curr Biol 2011, 21:1391–1396.
Ben‐Zvi, D, Barkai, N. Scaling of morphogen gradients by an expansion‐repression integral feedback control. Proc Natl Acad Sci USA 2010, 107:6924–6929.
McHale, P, Rappel, WJ, Levine, H. Embryonic pattern scaling achieved by oppositely directed morphogen gradients. Phys Biol 2006, 3:107–120.
Averbukh, I, Ben‐Zvi, D, Mishra, S, Barkai, N. Scaling morphogen gradients during tissue growth by a cell division rule. Development 2014, 141:2150–2156.
Vuilleumier, R, Springhorn, A, Patterson, L, Koidl, S, Hammerschmidt, M, Affolter, M, Pyrowolakis, G. Control of Dpp morphogen signalling by a secreted feedback regulator. Nat Cell Biol 2010, 12:611–617.
Akiyama, T, Kamimura, K, Firkus, C, Takeo, S, Shimmi, O, Nakato, H. Dally regulates Dpp morphogen gradient formation by stabilizing Dpp on the cell surface. Dev Biol 2008, 313:408–419.
Dupont, S, Morsut, L, Aragona, M, Enzo, E, Giulitti, S, Cordenonsi, M, Zanconato, F, Le Digabel, J, Forcato, M, Bicciato, S, et al. Role of YAP/TAZ in mechanotransduction. Nature 2011, 474:179–183.
Fernandez, BG, Gaspar, P, Bras‐Pereira, C, Jezowska, B, Rebelo, SR, Janody, F. Actin‐capping protein and the Hippo pathway regulate F‐actin and tissue growth in Drosophila. Development 2011, 138:2337–2346.
Sansores‐Garcia, L, Bossuyt, W, Wada, K, Yonemura, S, Tao, C, Sasaki, H, Halder, G. Modulating F‐actin organization induces organ growth by affecting the Hippo pathway. EMBO J 2011, 30:2325–2335.
Huang, J, Wu, S, Barrera, J, Matthews, K, Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 2005, 122:421–434.
Corrigall, D, Walther, RF, Rodriguez, L, Fichelson, P, Pichaud, F. Hedgehog signaling is a principal inducer of Myosin‐II‐driven cell ingression in Drosophila epithelia. Dev Cell 2007, 13:730–742.
Muller, B, Hartmann, B, Pyrowolakis, G, Affolter, M, Basler, K. Conversion of an extracellular Dpp/BMP morphogen gradient into an inverse transcriptional gradient. Cell 2003, 113:221–233.
Schwank, G, Yang, SF, Restrepo, S, Basler, K. Comment on ‘Dynamics of dpp signaling and proliferation control.’ Science 2012, 335:401; author reply 401.
Wartlick, O, Mamcu, P, Julicher, F, Gonzalez‐Gaitan, M. Response to comment on ‘Dynamics of Dpp signaling and proliferation control.’ Science 2012, 335:401.
Fu, W, Baker, NE. Deciphering synergistic and redundant roles of Hedgehog, Decapentaplegic and Delta that drive the wave of differentiation in Drosophila eye development. Development 2003, 130:5229–5239.

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