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Tissue remodelling through branching morphogenesis

Key Points

  • The tracheal system of Drosophila melanogaster is one of the best characterized multicellular branched organs. Branchless (BNL), a fibroblast growth factor (FGF) ligand, initiates the branching process by triggering cell migration, and functions at the top of a hierarchy of processes that orchestrate branching (for example, branch initiation, branch extension, cell competition, cell intercalation and cell determination).

  • Recent studies have unravelled unexpected similarities in cellular behaviour between tracheal branching in D. melanogaster and angiogenic sprouting in vertebrates. Vascular endothelial growth factor A (VEGFA), encoded by one of the four Vegf genes in mammals, is key to most of the morphogenetic events during angiogenesis that control migration, proliferation and survival of endothelial cells.

  • Tracheal system and vasculature development are conceptually different from lung and kidney development. The lung and kidney occupy a defined volume in an organism and the branching process is essentially limited to a 'bag' of mesenchymal tissue. Lung and kidney branching is controlled by various reciprocal feedback interactions between the branching epithelium and the surrounding mesenchyme. FGF and glial cell-derived neurotrophic factor (GDNF) in lung and kidney, respectively, are specifically expressed by the stroma in regions that prefigure branch outgrowth.

  • Mammary epithelial branching is also regulated by various signals expressed by the epithelium or the stroma, including bone morphogenetic protein (BMP), Wnt and epidermal growth factor (EGF) proteins. Moreover, hormonal control has an important role in mammary gland branching. However, in sharp contrast to the other branching processes, no signal has been identified that is specifically expressed by the stroma in regions that prefigure branch outgrowth. The mammary gland branching process therefore seems to be stochastic.

  • Growing branches are polarized through the establishment of a tip and a stalk. In the fly tracheal system and the vertebrate vasculature, a few cells or a single cell take up the lead position and are followed by stalk cells. Epithelial cells compete for leading positions. The cell interactions that determine the tip and stalk structures depend on Notch-dependent lateral inhibition at the single cell level.

  • In lung, kidney and mammary gland development, the cellular complexity is much higher than in the fly trachea and vertebrate vasculature as the branching tip is composed of many cells, which makes it unlikely that the Notch pathway is involved in the segregation of tip and stalk cells. Cell proliferation is a major factor contributing to elongation and branching in these complex systems.

Abstract

Branched structures are evident at all levels of organization in living organisms. Many organs, such as the vascular system, lung, kidney and mammary gland, are heavily branched. In each of these cases, equally fascinating questions have been put forward, including those that address the cellular and molecular mechanisms that regulate the branching process itself, such as where the branches are initiated and how they extend and grow in the right direction. Recent experiments suggest that cell competition and cell rearrangements might be conserved key features in branch formation and might be controlled by local cell signalling.

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Figure 1: Drosophila melanogaster trachea and vertebrate vasculature branching.
Figure 2: Lung patterning by iterative programming.
Figure 3: Molecular regulation of lung and kidney branching morphogenesis.

References

  1. 1

    Bryant, D. M. & Mostov, K. E. From cells to organs: building polarized tissue. Nature Rev. Mol. Cell Biol. 9, 887–901 (2008).

    CAS  Google Scholar 

  2. 2

    Chung, S. & Andrew, D. J. The formation of epithelial tubes. J. Cell Sci. 121, 3501–3504 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Hogan, B. L. M. & Kolodziej, P. A. Organogenesis: molecular mechanisms of tubulogenesis. Nature Rev. Genet. 3, 513–523 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Lecuit, T. & Goff, L. L. Orchestrating size and shape during morphogenesis. Nature 450, 189–192 (2007).

    CAS  PubMed  Google Scholar 

  5. 5

    Lubarsky, B. & Krasnow, M. A. Tube morphogenesis: making and shaping biological tubes. Cell 112, 19–28 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Affolter, M. & Caussinus, E. Tracheal branching morphogenesis in Drosophila: new insights into cell behaviour and organ architecture. Development 135, 2055–2064 (2008).

    CAS  Google Scholar 

  7. 7

    Ghabrial, A., Luschnig, S., Metzstein, M. M. & Krasnow, M. A. Branching morphogenesis of the Drosophila tracheal system. Annu. Rev. Cell Dev. Biol. 19, 623–647 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Uv, A., Cantera, R. & Samakovlis, C. Drosophila tracheal morphogenesis: intricate cellular solutions to basic plumbing problems. Trends Cell Biol. 13, 301–309 (2003).

    CAS  PubMed  Google Scholar 

  9. 9

    Klämbt, C., Glazer, L. & Shilo, B. Z. breathless, a Drosophila FGF receptor homolog, is essential for migration of tracheal and specific midline glial cells. Genes Dev. 6, 1668–1678 (1992).

    PubMed  Google Scholar 

  10. 10

    Sutherland, D., Samakovlis, C. & Krasnow, M. A. branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell 87, 1091–1101 (1996). A description of the D. melanogaster gene Bnl . BNL functions as a ligand for Breathless (an FGF receptor expressed on developing tracheal cells), is required for tracheal branching and is expressed dynamically in clusters of cells surrounding the tracheal system.

    CAS  Google Scholar 

  11. 11

    Ghabrial, A. S. & Krasnow, M. A. Social interactions among epithelial cells during tracheal branching morphogenesis. Nature 441, 746–749 (2006). Shows that cell competition creates two distinct classes of cells in developing D. melanogaster tracheal branches. Cells with the highest FGFR activity are at the tip, whereas those with less FGFR activity form the branch stalk.

    CAS  Google Scholar 

  12. 12

    Ribeiro, C., Neumann, M. & Affolter, M. Genetic control of cell intercalation during tracheal morphogenesis in Drosophila. Curr. Biol. 14, 2197–2207 (2004).

    CAS  PubMed  Google Scholar 

  13. 13

    Caussinus, E., Colombelli, J. & Affolter, M. Tip-cell migration controls stalk-cell intercalation during Drosophila tracheal tube elongation. Curr. Biol. 18, 1727–1734 (2008). Identifies the major forces that contribute to D. melanogaster tracheal branch remodelling. One or two leading cells produce enough mechanical power to intercalate many lagging cells.

    CAS  Google Scholar 

  14. 14

    Jarecki, J., Johnson, E. & Krasnow, M. A. Oxygen regulation of airway branching in Drosophila is mediated by branchless FGF. Cell 99, 211–220 (1999).

    CAS  PubMed  Google Scholar 

  15. 15

    Centanin, L. et al. Cell autonomy of HIF effects in Drosophila: tracheal cells sense hypoxia and induce terminal branch sprouting. Dev. Cell 14, 547–558 (2008).

    CAS  PubMed  Google Scholar 

  16. 16

    Brodu, V. & Casanova, J. The RhoGAP crossveinless-c links trachealess and EGFR signaling to cell shape remodeling in Drosophila tracheal invagination. Genes Dev. 20, 1817–1828 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Englund, C., Steneberg, P., Falileeva, L., Xylourgidis, N. & Samakovlis, C. Attractive and repulsive functions of Slit are mediated by different receptors in the Drosophila trachea. Development 129, 4941–4951 (2002).

    CAS  PubMed  Google Scholar 

  18. 18

    Kato, K., Chihara, T. & Hayashi, S. Hedgehog and Decapentaplegic instruct polarized growth of cell extensions in the Drosophila trachea. Development 131, 5253–5261 (2004).

    CAS  PubMed  Google Scholar 

  19. 19

    Llimargas, M. & Casanova, J. EGF signalling regulates cell invagination as well as cell migration during formation of tracheal system in Drosophila. Dev. Genes Evol. 209, 174–179 (1999).

    CAS  PubMed  Google Scholar 

  20. 20

    Vincent, S. et al. DPP controls tracheal cell migration along the dorsoventral body axis of the Drosophila embryo. Development 124, 2741–2750 (1997).

    CAS  PubMed  Google Scholar 

  21. 21

    Dickson, B. J. & Gilestro, G. F. Regulation of commissural axon pathfinding by slit and its Robo receptors. Annu. Rev. Cell Dev. Biol. 22, 651–675 (2006).

    CAS  PubMed  Google Scholar 

  22. 22

    Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Coultas, L., Chawengsaksophak, K. & Rossant, J. Endothelial cells and VEGF in vascular development. Nature 438, 937–945 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Ferrara, N., Gerber, H.-P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003).

    CAS  PubMed  Google Scholar 

  25. 25

    Lohela, M., Bry, M., Tammela, T. & Alitalo, K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr. Opin. Cell Biol. 21, 154–165 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Ruhrberg, C. Growing and shaping the vascular tree: multiple roles for VEGF. Bioessays 25, 1052–1060 (2003).

    CAS  PubMed  Google Scholar 

  27. 27

    Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol. 161, 1163–1177 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Gerhardt, H. VEGF and endothelial guidance in angiogenic sprouting. Organogenesis 4, 241–246 (2008).

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Hellström, M. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007).

    PubMed  Google Scholar 

  30. 30

    Leslie, J. D. et al. Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 134, 839–844 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Liu, Z.-J. et al. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol. Cell. Biol. 23, 14–25 (2003).

    PubMed  PubMed Central  Google Scholar 

  32. 32

    Shutter, J. R. et al. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev. 14, 1313–1318 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Siekmann, A. F. & Lawson, N. D. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445, 781–784 (2007).

    CAS  Google Scholar 

  34. 34

    Williams, C. K., Li, J.-L., Murga, M., Harris, A. L. & Tosato, G. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107, 931–939 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Dufraine, J., Funahashi, Y. & Kitajewski, J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27, 5132–5137 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Roca, C. & Adams, R. H. Regulation of vascular morphogenesis by Notch signaling. Genes Dev. 21, 2511–2524 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Fraisl, P., Mazzone, M., Schmidt, T. & Carmeliet, P. Regulation of angiogenesis by oxygen and metabolism. Dev. Cell 16, 167–179 (2009).

    CAS  Google Scholar 

  38. 38

    Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).

    CAS  PubMed  Google Scholar 

  39. 39

    Larrivée, B., Freitas, C., Suchting, S., Brunet, I. & Eichmann, A. Guidance of vascular development: lessons from the nervous system. Circ. Res. 104, 428–441 (2009).

    PubMed  Google Scholar 

  40. 40

    Metzger, R. J., Klein, O. D., Martin, G. R. & Krasnow, M. A. The branching programme of mouse lung development. Nature 453, 745–750 (2008). Reconstructs the complete 3D branching pattern and lineage of the mouse bronchial tree, up to the pseudoglandular stage, which turns out to be remarkably stereotyped.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Ackerman, K. G. et al. Gata4 is necessary for normal pulmonary lobar development. Am. J. Respir. Cell Mol. Biol. 36, 391–397 (2007).

    CAS  PubMed  Google Scholar 

  42. 42

    Cardoso, W. V. & Lü, J. Regulation of early lung morphogenesis: questions, facts and controversies. Development 133, 1611–1624 (2006).

    CAS  PubMed  Google Scholar 

  43. 43

    Horowitz, A. & Simons, M. Branching morphogenesis. Circ. Res. 103, 784–795 (2008).

    CAS  PubMed  Google Scholar 

  44. 44

    Bellusci, S., Grindley, J., Emoto, H., Itoh, N. & Hogan, B. L. Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 124, 4867–4878 (1997).

    CAS  PubMed  Google Scholar 

  45. 45

    Moerlooze, L. D. et al. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal–epithelial signalling during mouse organogenesis. Development 127, 483–492 (2000).

    PubMed  Google Scholar 

  46. 46

    Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nature Genet. 21, 138–141 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Mailleux, A. A. et al. Evidence that SPROUTY2 functions as an inhibitor of mouse embryonic lung growth and morphogenesis. Mech. Dev. 102, 81–94 (2001).

    CAS  PubMed  Google Scholar 

  48. 48

    Tefft, J. D. et al. Conserved function of mSpry-2, a murine homolog of Drosophila sprouty, which negatively modulates respiratory organogenesis. Curr. Biol. 9, 219–222 (1999).

    CAS  PubMed  Google Scholar 

  49. 49

    Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. & Hogan, B. L. Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. Development 122, 1693–1702 (1996).

    CAS  PubMed  Google Scholar 

  50. 50

    Eblaghie, M. C., Reedy, M., Oliver, T., Mishina, Y. & Hogan, B. L. Evidence that autocrine signaling through Bmpr1a regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells. Dev. Biol. 291, 67–82 (2006).

    CAS  PubMed  Google Scholar 

  51. 51

    Lebeche, D., Malpel, S. & Cardoso, W. V. Fibroblast growth factor interactions in the developing lung. Mech. Dev. 86, 125–136 (1999).

    CAS  PubMed  Google Scholar 

  52. 52

    Chuang, P.-T., Kawcak, T. N. & McMahon, A. P. Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung. Genes Dev. 17, 342–347 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Liu, Y. et al. Novel role for Netrins in regulating epithelial behavior during lung branching morphogenesis. Curr. Biol. 14, 897–905 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Mucenski, M. L. et al. β-Catenin is required for specification of proximal/distal cell fate during lung morphogenesis. J. Biol. Chem. 278, 40231–40238 (2003).

    CAS  PubMed  Google Scholar 

  55. 55

    Shu, W. et al. Wnt/β-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal–distal patterning in the lung. Dev. Biol. 283, 226–239 (2005).

    CAS  PubMed  Google Scholar 

  56. 56

    Dressler, G. R. The cellular basis of kidney development. Annu. Rev. Cell Dev. Biol. 22, 509–529 (2006).

    CAS  PubMed  Google Scholar 

  57. 57

    Kopan, R., Cheng, H.-T. & Surendran, K. Molecular insights into segmentation along the proximal–distal axis of the nephron. J. Am. Soc. Nephrol 18, 2014–2020 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Quaggin, S. E. & Kreidberg, J. A. Development of the renal glomerulus: good neighbors and good fences. Development 135, 609–620 (2008).

    CAS  PubMed  Google Scholar 

  59. 59

    Costantini, F. Renal branching morphogenesis: concepts, questions, and recent advances. Differentiation 74, 402–421 (2006).

    CAS  PubMed  Google Scholar 

  60. 60

    Watanabe, T. & Costantini, F. Real-time analysis of ureteric bud branching morphogenesis in vitro. Dev. Biol. 271, 98–108 (2004).

    CAS  PubMed  Google Scholar 

  61. 61

    al Awqati, Q. & Goldberg, M. R. Architectural patterns in branching morphogenesis in the kidney. Kidney Int. 54, 1832–1842 (1998).

    CAS  PubMed  Google Scholar 

  62. 62

    Costantini, F. & Shakya, R. GDNF/Ret signaling and the development of the kidney. Bioessays 28, 117–127 (2006).

    CAS  PubMed  Google Scholar 

  63. 63

    Shakya, R., Watanabe, T. & Costantini, F. The role of GDNF/Ret signaling in ureteric bud cell fate and branching morphogenesis. Dev. Cell 8, 65–74 (2005).

    CAS  Google Scholar 

  64. 64

    Chi, X. et al. Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev. Cell 17, 199–209 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Shakya, R. et al. The role of GDNF in patterning the excretory system. Dev. Biol. 283, 70–84 (2005). Shows the contribution of RET-dependent cell movements and RET-independent epithelial transitions in the Wolffian duct in the formation of the ureteric bud.

    CAS  PubMed  Google Scholar 

  66. 66

    Grieshammer, U. et al. SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site. Dev. Cell 6, 709–717 (2004).

    CAS  PubMed  Google Scholar 

  67. 67

    Basson, M. A. et al. Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev. Cell 8, 229–239 (2005).

    CAS  PubMed  Google Scholar 

  68. 68

    Majumdar, A., Vainio, S., Kispert, A., McMahon, J. & McMahon, A. P. Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. Development 130, 3175–3185 (2003).

    CAS  PubMed  Google Scholar 

  69. 69

    Michos, O. et al. Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis. Development 134, 2397–2405 (2007).

    CAS  PubMed  Google Scholar 

  70. 70

    Michos, O. et al. Gremlin-mediated BMP antagonism induces the epithelial–mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development 131, 3401–3410 (2004).

    CAS  PubMed  Google Scholar 

  71. 71

    Miyazaki, Y., Oshima, K., Fogo, A., Hogan, B. L. & Ichikawa, I. Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter. J. Clin. Invest. 105, 863–873 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Ohuchi, H. et al. FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem. Biophys. Res. Commun. 277, 643–649 (2000).

    CAS  PubMed  Google Scholar 

  73. 73

    Qiao, J. et al. FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development 126, 547–554 (1999).

    CAS  PubMed  Google Scholar 

  74. 74

    Zhao, H. et al. Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev. Biol. 276, 403–415 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Bénazet, J.-D. et al. A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning. Science 323, 1050–1053 (2009). An interesting example of epithelial–mesenchymal feedback loops between SHH and FGF signalling, involving the BMP antagonist gremlin 1. This self-regulatory signalling network results in the robust regulation of mouse distal limb development.

    Google Scholar 

  76. 76

    Chu, E. Y. et al. Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 131, 4819–4829 (2004).

    CAS  PubMed  Google Scholar 

  77. 77

    Veltmaat, J. M. et al. Gli3-mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes. Development 133, 2325–2335 (2006).

    CAS  PubMed  Google Scholar 

  78. 78

    Hinck, L. & Silberstein, G. B. Key stages in mammary gland development: the mammary end bud as a motile organ. Breast Cancer Res. 7, 245–251 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Sternlicht, M. D., Kouros-Mehr, H., Lu, P. & Werb, Z. Hormonal and local control of mammary branching morphogenesis. Differentiation 74, 365–381 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Watson, C. J. & Khaled, W. T. Mammary development in the embryo and adult: a journey of morphogenesis and commitment. Development 135, 995–1003 (2008).

    CAS  Google Scholar 

  81. 81

    Hens, J. R. et al. BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction. Development 134, 1221–1230 (2007).

    CAS  PubMed  Google Scholar 

  82. 82

    Hens, J. R. & Wysolmerski, J. J. Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland. Breast Cancer Res. 7, 220–224 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Moraes, R. C. et al. Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia. Development 134, 1231–1242 (2007).

    CAS  PubMed  Google Scholar 

  84. 84

    Bocchinfuso, W. P. et al. Induction of mammary gland development in estrogen receptor-α knockout mice. Endocrinology 141, 2982–2994 (2000).

    CAS  PubMed  Google Scholar 

  85. 85

    Brisken, C. et al. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl Acad. Sci. USA 95, 5076–5081 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Feng, Y., Manka, D., Wagner, K.-U. & Khan, S. A. Estrogen receptor-α expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc. Natl Acad. Sci. USA 104, 14718–14723 (2007).

    CAS  Google Scholar 

  87. 87

    Mallepell, S., Krust, A., Chambon, P. & Brisken, C. Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland. Proc. Natl Acad. Sci. USA 103, 2196–2201 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Silberstein, G. B. Postnatal mammary gland morphogenesis. Microsc. Res. Tech. 52, 155–162 (2001).

    CAS  PubMed  Google Scholar 

  89. 89

    Nelson, C. M., Vanduijn, M. M., Inman, J. L., Fletcher, D. A. & Bissell, M. J. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science 314, 298–300 (2006). Shows that the geometry of mammary tubules dictates the position of branches. Mammary branches initiate at sites with a local minimum concentration of autocrine inhibitory morphogens, such as TGFβ.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Sagasti, A., Guido, M. R., Raible, D. W. & Schier, A. F. Repulsive interactions shape the morphologies and functional arrangement of zebrafish peripheral sensory arbors. Current biology 15, 804–814 (2005).

    CAS  PubMed  Google Scholar 

  91. 91

    Daniel, C. W., Robinson, S. & Silberstein, G. B. The role of TGF-β in patterning and growth of the mammary ductal tree. J. Mammary Gland Biol. Neoplasia 1, 331–341 (1996).

    CAS  Google Scholar 

  92. 92

    Ewan, K. B. et al. Latent transforming growth factor-β activation in mammary gland: regulation by ovarian hormones affects ductal and alveolar proliferation. Am. J. Pathol. 160, 2081–2093 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Ewald, A. J., Brenot, A., Duong, M., Chan, B. S. & Werb, Z. Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev. Cell 14, 570–581 (2008). Reports that mammary gland branching results from the active motility of both luminal and myoepithelial cells. Luminal epithelial cells advance collectively, whereas myoepithelial cells seem to restrain elongating ducts.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Parsa, S. et al. Terminal end bud maintenance in mammary gland is dependent upon FGFR2b signaling. Dev. Biol. 317, 121–131 (2008).

    CAS  Google Scholar 

  95. 95

    Lu, P., Ewald, A. J., Martin, G. R. & Werb, Z. Genetic mosaic analysis reveals FGF receptor 2 function in terminal end buds during mammary gland branching morphogenesis. Dev. Biol. 321, 77–87 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Lecuit, T. & Lenne, P.-F. Cell surface mechanics and the control of cell shape, tissue patterns and morphogenesis. Nature Rev. Mol. Cell Biol. 8, 633–644 (2007).

    CAS  Google Scholar 

  97. 97

    Farhadifar, R., Röper, J.-C., Aigouy, B., Eaton, S. & Jülicher, F. The influence of cell mechanics, cell–cell interactions, and proliferation on epithelial packing. Curr. Biol. 17, 2095–2104 (2007).

    CAS  PubMed  Google Scholar 

  98. 98

    Rauzi, M., Verant, P., Lecuit, T. & Lenne, P.-F. Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis. Nature Cell Biol. 10, 1401–1410 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Desprat, N., Supatto, W., Pouille, P.-A., Beaurepaire, E. & Farge, E. Tissue deformation modulates twist expression to determine anterior midgut differentiation in Drosophila embryos. Dev. Cell 15, 470–477 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Colombelli, J. et al. Mechanosensing in actin stress fibers revealed by a close correlation between force and protein localization. J. Cell Sci. 122, 1665–1679 (2009).

    CAS  PubMed  Google Scholar 

  101. 101

    Hutson, M. S. et al. Forces for morphogenesis investigated with laser microsurgery and quantitative modeling. Science 300, 145–149 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Kiehart, D. P., Galbraith, C. G., Edwards, K. A., Rickoll, W. L. & Montague, R. A. Multiple forces contribute to cell sheet morphogenesis for dorsal closure in Drosophila. J. Cell Biol. 149, 471–490 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Vogel, A. & Venugopalan, V. Mechanisms of pulsed laser ablation of biological tissues. Chem. Rev. 103, 577–644 (2003).

    CAS  PubMed  Google Scholar 

  104. 104

    Solon, J., Kaya-Copur, A., Colombelli, J. & Brunner, D. Pulsed forces timed by a ratchet-like mechanism drive directed tissue movement during dorsal closure. Cell 137, 1331–1342 (2009).

    Google Scholar 

  105. 105

    Bénazet, J. D. & Zeller, R. Vertebrate limb development: moving from classical morphogen gradients to an integrated 4D patterning system. Cold Spring Harb. Perspect. Biol. 1 a001339 (2009).

    PubMed  PubMed Central  Google Scholar 

  106. 106

    Scherz, P. J., Harfe, B. D., McMahon, A. P. & Tabin, C. J. The limb bud Shh–Fgf feedback loop is terminated by expansion of former ZPA cells. Science 305, 396–399 (2004).

    CAS  PubMed  Google Scholar 

  107. 107

    Verheyden, J. M. & Sun, X. An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowth. Nature 454, 638–641 (2008). An interesting example of a self-promoting and self-terminating circuit that might be used to attain proper tissue size in a range of developmental and regenerative settings.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Smet, I. D. & Jürgens, G. Patterning the axis in plants — auxin in control. Curr. Opin. Genet. Dev. 17, 337–343 (2007).

    PubMed  Google Scholar 

  109. 109

    Bayer, E. M. et al. Integration of transport-based models for phyllotaxis and midvein formation. Genes Dev. 23, 373–384 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Kuhlemeier, C. Phyllotaxis. Trends Plant Sci. 12, 143–150 (2007).

    CAS  PubMed  Google Scholar 

  111. 111

    Reinhardt, D. et al. Regulation of phyllotaxis by polar auxin transport. Nature 426, 255–260 (2003).

    CAS  PubMed  Google Scholar 

  112. 112

    Smith, R. S. et al. A plausible model of phyllotaxis. Proc. Natl Acad. Sci. USA 103, 1301–1306 (2006).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank H. Gerhardt, R. Metzger, Z. Werb, F. Costantini, C. Kuehlemeier and R. Smith for stimulating discussions. We apologize for not being able to cite all relevant primary publications because of space restrictions.

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Correspondence to Markus Affolter.

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Glossary

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E-cadherin

The major Ca2+-dependent cell–cell adhesion molecule involved in the establishment of embryonic epithelium and in ensuring that epithelial cells remain bound together.

Ectoderm

The epithelium that covers the body surface of the early embryo.

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Tracheal sac

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A thin, dynamic cytoplasmic projection covered with cell membrane that extends from the leading edge of migrating cells. Filopodia contain actin filament bundles and are presumably involved in exploring the cell environment.

Intercalation

The process during which cells insert between cells that are already in contact with each other.

Chemoattractant

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Hypoxia

The lack of an adequate oxygen supply to an area of the body.

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The growth of new blood vessels from pre-existing vessels.

Astrocyte

A star-shaped cell that provides support and protection for neurons in the central nervous system.

Intersegmental vessel

A vessel that carries blood from the dorsal aorta between somites to the dorsal side of the neural tube.

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Apical ectodermal ridge

The thickening of the ectoderm rim at the tip of a developing limb bud in a vertebrate embryo.

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Affolter, M., Zeller, R. & Caussinus, E. Tissue remodelling through branching morphogenesis. Nat Rev Mol Cell Biol 10, 831–842 (2009). https://doi.org/10.1038/nrm2797

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