Cell and Tissue Research

, Volume 354, Issue 2, pp 343–354 | Cite as

Novel mechanisms of tube-size regulation revealed by the Drosophila trachea

  • Li Zuo
  • Ekaterini Iordanou
  • Rachana R. Chandran
  • Lan Jiang


The size of various tubes within tubular organs such as the lung, vascular system and kidney must be finely tuned for the optimal delivery of gases, nutrients, waste and cells within the entire organism. Aberrant tube sizes lead to devastating human illnesses, such as polycystic kidney disease, fibrocystic breast disease, pancreatic cystic neoplasm and thyroid nodules. However, the underlying mechanisms that are responsible for tube-size regulation have yet to be fully understood. Therefore, no effective treatments are available for disorders caused by tube-size defects. Recently, the Drosophila tracheal system has emerged as an excellent in vivo model to explore the fundamental mechanisms of tube-size regulation. Here, we discuss the role of the apical luminal matrix, cell polarity and signaling pathways in regulating tube size in Drosophila trachea. Previous studies of the Drosophila tracheal system have provided general insights into epithelial tube morphogenesis. Mechanisms that regulate tube size in Drosophila trachea could be well conserved in mammalian tubular organs. This knowledge should greatly aid our understanding of tubular organogenesis in vertebrates and potentially lead to new avenues for the treatment of human disease caused by tube-size defects.


Trachea Tube size Luminal matrix Apical secretion Cell polarity Endocytosis Drosophila 


  1. Adler PN (2002) Planar signaling and morphogenesis in Drosophila. Dev Cell 2:525-535PubMedCrossRefGoogle Scholar
  2. Adler PN (2012) The frizzled/stan pathway and planar cell polarity in the Drosophila wing. Curr Top Dev Biol 101:1–31PubMedCrossRefGoogle Scholar
  3. Affolter M, Nellen D, Nussbaumer U, Basler K (1994) Multiple requirements for the receptor serine/threonine kinase thick veins reveal novel functions of TGF beta homologs during Drosophila embryogenesis. Development 120:3105–3117PubMedGoogle Scholar
  4. Araujo SJ, Aslam H, Tear G, Casanova J (2005) Mummy/cystic encodes an enzyme required for chitin and glycan synthesis, involved in trachea, embryonic cuticle and CNS development—analysis of its role in Drosophila tracheal morphogenesis. Dev Biol 288:179–193PubMedCrossRefGoogle Scholar
  5. Armbruster K, Luschnig S (2012) The Drosophila Sec7 domain guanine nucleotide exchange factor protein Gartenzwerg localizes at the cis-Golgi and is essential for epithelial tube expansion. J Cell Sci 125:1318–1328PubMedCrossRefGoogle Scholar
  6. Aspenstrom P, Richnau N, Johansson AS (2006) The diaphanous-related formin DAAM1 collaborates with the Rho GTPases RhoA and Cdc42, CIP4 and Src in regulating cell morphogenesis and actin dynamics. Exp Cell Res 312:2180–2194PubMedCrossRefGoogle Scholar
  7. Bagnat M, Cheung ID, Mostov KE, Stainier DY (2007) Genetic control of single lumen formation in the zebrafish gut. Nat Cell Biol 9:954–960PubMedCrossRefGoogle Scholar
  8. Barbero P, Bittova L, Pfeffer SR (2002) Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells. J Cell Biol 156:511–518PubMedCrossRefGoogle Scholar
  9. Bastock R, Strutt D (2007) The planar polarity pathway promotes coordinated cell migration during Drosophila oogenesis. Development 134:3055-3064PubMedCrossRefGoogle Scholar
  10. Behr M, Riedel D, Schuh R (2003) The claudin-like megatrachea is essential in septate junctions for the epithelial barrier function in Drosophila. Dev Cell 5:611-620PubMedCrossRefGoogle Scholar
  11. Beitel GJ, Krasnow MA (2000) Genetic control of epithelial tube size in the Drosophila tracheal system. Development 127:3271–3282PubMedGoogle Scholar
  12. Blum Y, Belting HG, Ellertsdottir E, Herwig L, Luders F, Affolter M (2008) Complex cell rearrangements during intersegmental vessel sprouting and vessel fusion in the zebrafish embryo. Dev Biol 316:312–322PubMedCrossRefGoogle Scholar
  13. Bonifacino JS, Glick BS (2004) The mechanisms of vesicle budding and fusion. Cell 116:153–166PubMedCrossRefGoogle Scholar
  14. Bonifacino JS, Rojas R (2006) Retrograde transport from endosomes to the trans-Golgi network. Nat Rev Mol Cell Biol 7:568–579PubMedCrossRefGoogle Scholar
  15. Chia PZ, Gasnereau I, Lieu ZZ, Gleeson PA (2011) Rab9-dependent retrograde transport and endosomal sorting of the endopeptidase furin. J Cell Sci 124:2401–2413PubMedCrossRefGoogle Scholar
  16. Chihara T, Hayashi S (2000) Control of tracheal tubulogenesis by Wingless signaling. Development 127:4433–4442PubMedGoogle Scholar
  17. Chung S, Vining MS, Bradley PL, Chan CC, Wharton KA Jr, Andrew DJ (2009) Serrano (sano) functions with the planar cell polarity genes to control tracheal tube length. PLoS Genet 5:e1000746PubMedCrossRefGoogle Scholar
  18. Chung S, Chavez C, Andrew DJ (2011) Trachealess (Trh) regulates all tracheal genes during Drosophila embryogenesis. Dev Biol 360:160–172PubMedGoogle Scholar
  19. Colas JF, Schoenwolf GC (2001) Towards a cellular and molecular understanding of neurulation. Dev Dyn 221:117–145PubMedCrossRefGoogle Scholar
  20. Courbard JR, Djiane A, Wu J, Mlodzik M (2009) The apical/basal-polarity determinant Scribble cooperates with the PCP core factor Stbm/Vang and functions as one of its effectors. Dev Biol 333:67–77PubMedCrossRefGoogle Scholar
  21. Davis GE, Stratman AN, Sacharidou A, Koh W (2011) Molecular basis for endothelial lumen formation and tubulogenesis during vasculogenesis and angiogenic sprouting. Int Rev Cell Mol Biol 288:101–165PubMedCrossRefGoogle Scholar
  22. de Celis JF, Llimargas M, Casanova J (1995) Ventral veinless, the gene encoding the Cf1a transcription factor, links positional information and cell differentiation during embryonic and imaginal development in Drosophila melanogaster. Development 121:3405–3416PubMedGoogle Scholar
  23. Devine WP, Lubarsky B, Shaw K, Luschnig S, Messina L, Krasnow MA (2005) Requirement for chitin biosynthesis in epithelial tube morphogenesis. Proc Natl Acad Sci USA 102:17014–17019PubMedCrossRefGoogle Scholar
  24. Djiane A, Yogev S, Mlodzik M (2005) The apical determinants aPKC and dPatj regulate Frizzled-dependent planar cell polarity in the Drosophila eye. Cell 121:621–631PubMedCrossRefGoogle Scholar
  25. Dong B, Kakihara K, Otani T, Wada H, Hayashi S (2013) Rab9 and retromer regulate retrograde trafficking of luminal protein required for epithelial tube length control. Nat Commun 4:1358PubMedCrossRefGoogle Scholar
  26. Folkman J, Haudenschild C (1980) Angiogenesis in vitro. Nature 288:551–556PubMedCrossRefGoogle Scholar
  27. Forster D, Luschnig S (2012) Src42A-dependent polarized cell shape changes mediate epithelial tube elongation in Drosophila. Nat Cell Biol 14:526–534PubMedCrossRefGoogle Scholar
  28. Forster D, Armbruster K, Luschnig S (2010) Sec24-dependent secretion drives cell-autonomous expansion of tracheal tubes in Drosophila. Curr Biol 20:62–68PubMedCrossRefGoogle Scholar
  29. Garud SS, Willingham FF (2012) Molecular analysis of cyst fluid aspiration in the diagnosis and risk assessment of cystic lesions of the pancreas. Clin Transl Sci 5:102–107PubMedCrossRefGoogle Scholar
  30. Gerke V, Creutz CE, Moss SE (2005) Annexins: linking Ca2+ signalling to membrane dynamics. Nat Rev Mol Cell Biol 6:449–461PubMedCrossRefGoogle Scholar
  31. Ghabrial A, Luschnig S, Metzstein MM, Krasnow MA (2003) Branching morphogenesis of the Drosophila tracheal system. Annu Rev Cell Dev Biol 19:623–647PubMedCrossRefGoogle Scholar
  32. Grieder NC, Caussinus E, Parker DS, Cadigan K, Affolter M, Luschnig S (2008) gammaCOP is required for apical protein secretion and epithelial morphogenesis in Drosophila melanogaster. PLoS One 3:e3241PubMedCrossRefGoogle Scholar
  33. He B, Guo W (2009) The exocyst complex in polarized exocytosis. Curr Opin Cell Biol 21:537–542PubMedCrossRefGoogle Scholar
  34. Isaac DD, Andrew DJ (1996) Tubulogenesis in Drosophila: a requirement for the trachealess gene product. Genes Dev 10:103–117PubMedCrossRefGoogle Scholar
  35. Jacob R, Heine M, Eikemeyer J, Frerker N, Zimmer KP, Rescher U, Gerke V, Naim HY (2004) Annexin II is required for apical transport in polarized epithelial cells. J Biol Chem 279:3680–3684PubMedCrossRefGoogle Scholar
  36. Jayaram SA, Senti KA, Tiklova K, Tsarouhas V, Hemphala J, Samakovlis C (2008) COPI vesicle transport is a common requirement for tube expansion in Drosophila. PLoS One 3:e1964PubMedCrossRefGoogle Scholar
  37. Jazwinska A, Affolter M (2004) A family of genes encoding zona pellucida (ZP) domain proteins is expressed in various epithelial tissues during Drosophila embryogenesis. Gene Expr Patterns 4:413–421PubMedCrossRefGoogle Scholar
  38. Jenny A (2010) Planar cell polarity signaling in the Drosophila eye. Curr Top Dev Biol 93:189–227PubMedCrossRefGoogle Scholar
  39. Jeon M, Zinn K (2009) Receptor tyrosine phosphatases control tracheal tube geometries through negative regulation of EGFR signaling. Development 136:3121–3129PubMedCrossRefGoogle Scholar
  40. Jeon M, Scott MP, Zinn K (2012) Interactions between Type III receptor tyrosine phosphatases and growth factor receptor tyrosine kinases regulate tracheal tube formation in Drosophila. Biol Open 1:548–558PubMedCrossRefGoogle Scholar
  41. Jiang L, Crews ST (2006) Dysfusion transcriptional control of Drosophila tracheal migration, adhesion, and fusion. Mol Cell Biol 26:6547–6556PubMedCrossRefGoogle Scholar
  42. Jiang L, Rogers SL, Crews ST (2007) The Drosophila Dead end Arf-like3 GTPase controls vesicle trafficking during tracheal fusion cell morphogenesis. Dev Biol 311:487–499PubMedCrossRefGoogle Scholar
  43. Johannes L, Popoff V (2008) Tracing the retrograde route in protein trafficking. Cell 135:1175–1187PubMedCrossRefGoogle Scholar
  44. Johnson KG, Van Vactor D (2003) Receptor protein tyrosine phosphatases in nervous system development. Physiol Rev 83:1–24PubMedGoogle Scholar
  45. Kamei M, Saunders WB, Bayless KJ, Dye L, Davis GE, Weinstein BM (2006) Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442:453–456PubMedCrossRefGoogle Scholar
  46. Kato S, Sekine K (1999) FGF-FGFR signaling in vertebrate organogenesis. Cell Mol Biol (Noisy-le-grand) 45:631–638Google Scholar
  47. Klein TJ, Mlodzik M (2005) Planar cell polarization: an emerging model points in the right direction. Annu Rev Cell Dev Biol 21:155-176PubMedCrossRefGoogle Scholar
  48. Laprise P, Tepass U (2011) Novel insights into epithelial polarity proteins in Drosophila. Trends Cell Biol 21:401-408PubMedCrossRefGoogle Scholar
  49. Laprise P, Paul SM, Boulanger J, Robbins RM, Beitel GJ, Tepass U (2010) Epithelial polarity proteins regulate Drosophila tracheal tube size in parallel to the luminal matrix pathway. Curr Biol 20:55-61PubMedCrossRefGoogle Scholar
  50. Lawson ND, Weinstein BM (2002) In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248:307–318PubMedCrossRefGoogle Scholar
  51. Lebeche D, Malpel S, Cardoso WV (1999) Fibroblast growth factor interactions in the developing lung. Mech Dev 86:125–136PubMedCrossRefGoogle Scholar
  52. Lee S, Kolodziej PA (2002) The plakin Short Stop and the RhoA GTPase are required for E-cadherin-dependent apical surface remodeling during tracheal tube fusion. Development 129:1509–1520PubMedCrossRefGoogle Scholar
  53. Levi BP, Ghabrial AS, Krasnow MA (2006) Drosophila talin and integrin genes are required for maintenance of tracheal terminal branches and luminal organization. Development 133:2383–2393PubMedCrossRefGoogle Scholar
  54. Li J, Li W, Calhoun HC, Xia F, Gao FB, Li WX (2003) Patterns and functions of STAT activation during Drosophila embryogenesis. Mech Dev 120:1455–1468PubMedCrossRefGoogle Scholar
  55. Llimargas M (2000) Wingless and its signalling pathway have common and separable functions during tracheal development. Development 127:4407–4417PubMedGoogle Scholar
  56. Llimargas M, Casanova J (1999) EGF signalling regulates cell invagination as well as cell migration during formation of tracheal system in Drosophila. Dev Genes Evol 209:174–179PubMedCrossRefGoogle Scholar
  57. Llimargas M, Strigini M, Katidou M, Karagogeos D, Casanova J (2004) Lachesin is a component of a septate junction-based mechanism that controls tube size and epithelial integrity in the Drosophila tracheal system. Development 131:181-190PubMedCrossRefGoogle Scholar
  58. Lombardi D, Soldati T, Riederer MA, Goda Y, Zerial M, Pfeffer SR (1993) Rab9 functions in transport between late endosomes and the trans Golgi network. EMBO J 12:677–682PubMedGoogle Scholar
  59. Luschnig S, Batz T, Armbruster K, Krasnow MA (2006) Serpentine and vermiform encode matrix proteins with chitin binding and deacetylation domains that limit tracheal tube length in Drosophila. Curr Biol 16:186–194PubMedCrossRefGoogle Scholar
  60. Massarwa R, Schejter ED, Shilo BZ (2009) Apical secretion in epithelial tubes of the Drosophila embryo is directed by the Formin-family protein Diaphanous. Dev Cell 16:877–888PubMedCrossRefGoogle Scholar
  61. Matsuyama M, Aizawa S, Shimono A (2009) Sfrp controls apicobasal polarity and oriented cell division in developing gut epithelium. PLoS Genet 5:e1000427PubMedCrossRefGoogle Scholar
  62. Mellman I, Nelson WJ (2008) Coordinated protein sorting, targeting and distribution in polarized cells. Nat Rev Mol Cell Biol 9:833–845PubMedCrossRefGoogle Scholar
  63. Morrison DK, Murakami MS, Cleghon V (2000) Protein kinases and phosphatases in the Drosophila genome. J Cell Biol 150:F57–F62PubMedCrossRefGoogle Scholar
  64. Moussian B, Tang E, Tonning A, Helms S, Schwarz H, Nusslein-Volhard C, Uv AE (2006) Drosophila Knickkopf and Retroactive are needed for epithelial tube growth and cuticle differentiation through their specific requirement for chitin filament organization. Development 133:163–171PubMedCrossRefGoogle Scholar
  65. Moyer KE, Jacobs JR (2008) Varicose: a MAGUK required for the maturation and function of Drosophila septate junctions. BMC Dev Biol 8:99PubMedCrossRefGoogle Scholar
  66. Musch A, Cohen D, Yeaman C, Nelson WJ, Rodriguez-Boulan E, Brennwald PJ (2002) Mammalian homolog of Drosophila tumor suppressor lethal (2) giant larvae interacts with basolateral exocytic machinery in Madin-Darby canine kidney cells. Mol Biol Cell 13:158–168PubMedCrossRefGoogle Scholar
  67. Myat MM, Lightfoot H, Wang P, Andrew DJ (2005) A molecular link between FGF and Dpp signaling in branch-specific migration of the Drosophila trachea. Dev Biol 281:38–52PubMedCrossRefGoogle Scholar
  68. Nelson KS, Khan Z, Molnar I, Mihaly J, Kaschube M, Beitel GJ (2012) Drosophila Src regulates anisotropic apical surface growth to control epithelial tube size. Nat Cell Biol 14:518–525PubMedCrossRefGoogle Scholar
  69. Norum M, Tang E, Chavoshi T, Schwarz H, Linke D, Uv A, Moussian B (2010) Trafficking through COPII stabilises cell polarity and drives secretion during Drosophila epidermal differentiation. PLoS One 5:e10802PubMedCrossRefGoogle Scholar
  70. Paul SM, Ternet M, Salvaterra PM, Beitel GJ (2003) The Na+/K+ ATPase is required for septate junction function and epithelial tube-size control in the Drosophila tracheal system. Development 130:4963-4974PubMedCrossRefGoogle Scholar
  71. Popoveniuc G, Jonklaas J (2012) Thyroid nodules. Med Clin North Am 96:329–349PubMedCrossRefGoogle Scholar
  72. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, Oude Egbrink MG (2007) The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 454:345–359PubMedCrossRefGoogle Scholar
  73. Ribeiro C, Neumann M, Affolter M (2004) Genetic control of cell intercalation during tracheal morphogenesis in Drosophila. Curr Biol 14:2197–2207PubMedCrossRefGoogle Scholar
  74. Rinaldi P, Ierardi C, Costantini M, Magno S, Giuliani M, Belli P, Bonomo L (2010) Cystic breast lesions: sonographic findings and clinical management. J Ultrasound Med 29:1617–1626PubMedGoogle Scholar
  75. Saburi S, Hester I, Fischer E, Pontoglio M, Eremina V, Gessler M, Quaggin SE, Harrison R, Mount R, McNeill H (2008) Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat Genet 40:1010-1015PubMedCrossRefGoogle Scholar
  76. Samakovlis C, Hacohen N, Manning G, Sutherland D, Guillemin K, Krasnow MA (1996) Development of the Drosophila tracheal system occurs by a series of morphologically distinct but genetically coupled branching events. Development 122:1395–1407PubMedGoogle Scholar
  77. Schottenfeld-Roames J, Ghabrial AS (2012) Whacked and Rab35 polarize dynein-motor-complex-dependent seamless tube growth. Nat Cell Biol 14:386–393PubMedCrossRefGoogle Scholar
  78. Seifert JR, Mlodzik M (2007) Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nat Rev Genet 8:126-138PubMedCrossRefGoogle Scholar
  79. Shaye DD, Casanova J, Llimargas M (2008) Modulation of intracellular trafficking regulates cell intercalation in the Drosophila trachea. Nat Cell Biol 10:964–970PubMedCrossRefGoogle Scholar
  80. Sotillos S, Espinosa-Vazquez JM, Foglia F, Hu N, Hombria JC (2010) An efficient approach to isolate STAT regulated enhancers uncovers STAT92E fundamental role in Drosophila tracheal development. Dev Biol 340:571–582PubMedCrossRefGoogle Scholar
  81. Steinman TI (2012) Polycystic kidney disease: a 2011 update. Curr Opin Nephrol Hypertens 21:189–194PubMedCrossRefGoogle Scholar
  82. Sternlicht MD, Kouros-Mehr H, Lu P, Werb Z (2006) Hormonal and local control of mammary branching morphogenesis. Differentiation 74:365–381PubMedCrossRefGoogle Scholar
  83. Strilic B, Kucera T, Eglinger J, Hughes MR, McNagny KM, Tsukita S, Dejana E, Ferrara N, Lammert E (2009) The molecular basis of vascular lumen formation in the developing mouse aorta. Dev Cell 17:505–515PubMedCrossRefGoogle Scholar
  84. Strutt DI, Weber U, Mlodzik M (1997) The role of RhoA in tissue polarity and Frizzled signalling. Nature 387:292-295PubMedCrossRefGoogle Scholar
  85. Sutherland D, Samakovlis C, Krasnow MA (1996) Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell 87:1091–1101PubMedCrossRefGoogle Scholar
  86. Swanson LE, Beitel GJ (2006) Tubulogenesis: an inside job. Curr Biol 16:R51–R53PubMedCrossRefGoogle Scholar
  87. Tanaka-Matakatsu M, Uemura T, Oda H, Takeichi M, Hayashi S (1996) Cadherin-mediated cell adhesion and cell motility in Drosophila trachea regulated by the transcription factor Escargot. Development 122:3697–705PubMedGoogle Scholar
  88. Tepass U, Tanentzapf G, Ward R, Fehon R (2001) Epithelial cell polarity and cell junctions in Drosophila. Annu Rev Genet 35:747–784PubMedCrossRefGoogle Scholar
  89. Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13:513–609PubMedCrossRefGoogle Scholar
  90. Tonning A, Hemphala J, Tang E, Nannmark U, Samakovlis C, Uv A (2005) A transient luminal chitinous matrix is required to model epithelial tube diameter in the Drosophila trachea. Dev Cell 9:423–430PubMedCrossRefGoogle Scholar
  91. Tsarouhas V, Senti KA, Jayaram SA, Tiklova K, Hemphala J, Adler J, Samakovlis C (2007) Sequential pulses of apical epithelial secretion and endocytosis drive airway maturation in Drosophila. Dev Cell 13:214–225PubMedCrossRefGoogle Scholar
  92. Vincent S, Ruberte E, Grieder NC, Chen CK, Haerry T, Schuh R, Affolter M (1997) DPP controls tracheal cell migration along the dorsoventral body axis of the Drosophila embryo. Development 124:2741–2750PubMedGoogle Scholar
  93. Wang S, Jayaram SA, Hemphala J, Senti KA, Tsarouhas V, Jin H, Samakovlis C (2006) Septate-junction-dependent luminal deposition of chitin deacetylases restricts tube elongation in the Drosophila trachea. Curr Biol 16:180–185PubMedCrossRefGoogle Scholar
  94. Wickner W, Schekman R (2008) Membrane fusion. Nat Struct Mol Biol 15:658–664PubMedCrossRefGoogle Scholar
  95. Wilk R, Weizman I, Glazer L, Shilo B (1996) Trachealess encodes a bHLH-PAS protein and is a master regulator gene in the Drosophila tracheal system. Genes Dev 10:93–102PubMedCrossRefGoogle Scholar
  96. Wingen C, Aschenbrenner AC, Stumpges B, Hoch M, Behr M (2009) The Wurst protein: a novel endocytosis regulator involved in airway clearance and respiratory tube size control. Cell Adh Migr 3:14–18PubMedCrossRefGoogle Scholar
  97. Wu VM, Beitel GJ (2004) A junctional problem of apical proportions: epithelial tube-size control by septate junctions in the Drosophila tracheal system. Curr Opin Cell Biol 16:493-499PubMedCrossRefGoogle Scholar
  98. Wu VM, Schulte J, Hirschi A, Tepass U, Beitel GJ (2004) Sinuous is a Drosophila claudin required for septate junction organization and epithelial tube size control. J Cell Biol 164:313-323PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Li Zuo
    • 1
    • 2
  • Ekaterini Iordanou
    • 1
  • Rachana R. Chandran
    • 1
  • Lan Jiang
    • 1
    • 3
  1. 1.Department of Biological SciencesOakland UniversityRochesterUSA
  2. 2.School of Health and Rehabilitation Sciences, The Ohio State College of MedicineThe Ohio State University Wexner Medical CenterColumbusUSA
  3. 3.Dodge Hall of Engineering 322RochesterUSA

Personalised recommendations