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Retinoic acid regulates avian lung branching through a molecular network

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Abstract

Retinoic acid (RA) is of major importance during vertebrate embryonic development and its levels need to be strictly regulated otherwise congenital malformations will develop. Through the action of specific nuclear receptors, named RAR/RXR, RA regulates the expression of genes that eventually influence proliferation and tissue patterning. RA has been described as crucial for different stages of mammalian lung morphogenesis, and as part of a complex molecular network that contributes to precise organogenesis; nonetheless, nothing is known about its role in avian lung development. The current report characterizes, for the first time, the expression pattern of RA signaling members (stra6, raldh2, raldh3, cyp26a1, rarα, and rarβ) and potential RA downstream targets (sox2, sox9, meis1, meis2, tgfβ2, and id2) by in situ hybridization. In the attempt of unveiling the role of RA in chick lung branching, in vitro lung explants were performed. Supplementation studies revealed that RA stimulates lung branching in a dose-dependent manner. Moreover, the expression levels of cyp26a1, sox2, sox9, rarβ, meis2, hoxb5, tgfβ2, id2, fgf10, fgfr2, and shh were evaluated after RA treatment to disclose a putative molecular network underlying RA effect. In situ hybridization analysis showed that RA is able to alter cyp26a1, sox9, tgfβ2, and id2 spatial distribution; to increase rarβ, meis2, and hoxb5 expression levels; and has a very modest effect on sox2, fgf10, fgfr2, and shh expression levels. Overall, these findings support a role for RA in the proximal–distal patterning and branching morphogenesis of the avian lung and reveal intricate molecular interactions that ultimately orchestrate branching morphogenesis.

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References

  1. Maina JN (2006) Development, structure, and function of a novel respiratory organ, the lung-air sac system of birds: to go where no other vertebrate has gone. Biol Rev 81:545–579. doi:10.1017/S1464793106007111

    Article  PubMed  Google Scholar 

  2. Metzger RJ, Klein OD, Martin GR, Krasnow MA (2008) The branching programme of mouse lung development. Nature 453(7196):745–750. doi:10.1038/nature07005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sakiyama J, Yamagishi A, Kuroiwa A (2003) Tbx4-Fgf10 system controls lung bud formation during chicken embryonic development. Development 130(7):1225–1234. doi:10.1242/dev.00345

    Article  CAS  PubMed  Google Scholar 

  4. Moura RS, Coutinho-Borges JP, Pacheco AP, daMota PO, Correia-Pinto J (2011) FGF signaling pathway in the developing chick lung: expression and inhibition studies. PLoS One 6(3):e17660. doi:10.1371/journal.pone.0017660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Moura RS, Carvalho-Correia E, daMota P, Correia-Pinto J (2014) Canonical Wnt signaling activity in early stages of chick lung development. PLoS One 9(12):e112388. doi:10.1371/journal.pone.0112388

    Article  PubMed  PubMed Central  Google Scholar 

  6. Loscertales M, Mikels AJ, Hu JK, Donahoe PK, Roberts DJ (2008) Chick pulmonary Wnt5a directs airway and vascular tubulogenesis. Development 135(7):1365–1376. doi:10.1242/dev.010504

    Article  CAS  PubMed  Google Scholar 

  7. Moura RS, Silva-Gonçalves C, Vaz-Cunha P, Correia-Pinto J (2016) Expression analysis of Shh signaling members in early stages of chick lung development. Histochem Cell Biol 146(4):457–466. doi:10.1007/s00418-016-1448-1

    Article  CAS  PubMed  Google Scholar 

  8. Davey MG, McTeir L, Barrie AM, Freem LJ, Stephen LA (2014) Loss of cilia causes embryonic lung hypoplasia, liver fibrosis, and cholestasis in the talpid3 ciliopathy mutant. Organogenesis 10(2):177–185. doi:10.4161/org.28819

    Article  PubMed  PubMed Central  Google Scholar 

  9. Moura RS, Vaz-Cunha P, Silva-Gonçalves C, Correia-Pinto J (2015) Characterization of miRNA processing machinery in the embryonic chick lung. Cell Tissue Res 362(3):569–575. doi:10.1007/s00441-015-2240-6

    Article  CAS  PubMed  Google Scholar 

  10. Gleghorn JP, Kwak J, Pavlovich AL, Nelson CM (2012) Inhibitory morphogens and monopodial branching of the embryonic chicken lung. Dev Dyn 241(5):852–862. doi:10.1002/dvdy.23771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ornitz DM, Yin Y (2012) Signaling networks regulating development of the lower respiratory tract. Cold Spring Harb Perspect Biol 4(5):a008318. doi:10.1101/cshperspect.a008318

    Article  PubMed  PubMed Central  Google Scholar 

  12. Malpel S, Mendelsohn C, Cardoso WV (2000) Regulation of retinoic acid signaling during lung morphogenesis. Development 127(14):3057–3067

    CAS  PubMed  Google Scholar 

  13. Piairo P, Moura RS, Nogueira-Silva Correia-Pinto J (2011) The apelinergic system in the developing lung: expression and signaling. Peptides 32(12):2474–2483. doi:10.1016/j.peptides.2011.10.010

    Article  CAS  PubMed  Google Scholar 

  14. Nogueira-Silva C, Piairo P, Carvalho-Dias E, Peixoto FO, Moura RS, Correia-Pinto J (2012) Leukemia inhibitory factor in rat fetal lung development: expression and functional studies. PLoS One 7(1):e30517. doi:10.1371/journal.pone.0030517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rhinn M, Dollé P (2012) Retinoic acid signalling during development. Development 139(5):843–858. doi:10.1242/dev.065938

    Article  CAS  PubMed  Google Scholar 

  16. Cunningham TJ, Duester G (2015) Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat Rev Mol Cell Biol 16(2):110–123. doi:10.1038/nrm3932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Clagett-Dame M, Knutson D (2011) Vitamin A in reproduction and development. Nutrients 3(4):385–428. doi:10.3390/nu3040385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H (2007) A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 315(5813):820–825. doi:10.1126/science.1136244

    Article  CAS  PubMed  Google Scholar 

  19. Ross AC, Zolfaghari R (2011) Cytochrome P450s in the regulation of cellular retinoic acid metabolism. Annu Rev Nutr 31:65–87. doi:10.1146/annurev-nutr-072610-145127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Duester G (2008) Retinoic acid synthesis and signaling during early organogenesis. Cell 134(6):921–931. doi:10.1016/j.cell.2008.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wilson JG, Roth CB, Warkany J (1953) An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 92(2):189–217. doi:10.1002/aja.1000920202

    Article  CAS  PubMed  Google Scholar 

  22. Shenefelt RE (1972) Morphogenesis of malformations in hamsters caused by retinoic acid: relation to dose and stage at treatment. Teratology 5:103–118. doi:10.1002/tera.1420050115

    Article  CAS  PubMed  Google Scholar 

  23. Mendelsohn C, Lohnes D, Décimo D, Lufkin T, LeMeur M, Chambon P, Mark M (1994) Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120:2749–2771

    CAS  PubMed  Google Scholar 

  24. Niederreither K, Subbarayan V, Dollé P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21:444–448. doi:10.1038/7788

    Article  CAS  PubMed  Google Scholar 

  25. Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P, Dollé P (2002) Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nat Genet 31:84–88. doi:10.1038/ng876

    CAS  PubMed  Google Scholar 

  26. Wang Z, Dollé P, Cardoso WV, Niederreither K (2006) Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives. Dev Biol 297:433–445. doi:10.1016/j.ydbio.2006.05.019

    Article  CAS  PubMed  Google Scholar 

  27. Chen F, Cao Y, Qian J, Shao F, Niederreither K, Cardoso WV (2010) A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J Clin Investig 120(6):2040–2048. doi:10.1172/JCI40253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rankin SA, Han L, McCracken KW, Kenny AP, Anglin CT, Grigg EA, Crawford CM, Wells JM, Shannon JM, Zorn AM (2016) A retinoic acid-hedgehog cascade coordinates mesoderm-inducing signals and endoderm competence during lung specification. Cell Rep 16(1):66–78. doi:10.1016/j.celrep.2016.05.060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chazaud C, Dollé P, Rossant J, Mollard R (2003) Retinoic acid signaling regulates murine bronchial tubule formation. Mech Dev 120(6):691–700. doi:10.1016/S0925-4773(03)00048-0

    Article  CAS  PubMed  Google Scholar 

  30. Chen F, Marquez H, Kim YK, Qian J, Shao F, Fine A, Cruikshank WW, Quadro L, Cardoso WV (2014) Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice. J Clin Investig 124:801–811. doi:10.1172/JCI70291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hind M, Gilthorpe A, Stinchcombe S, Maden M (2009) Retinoid induction of alveolar regeneration: from mice to man? Thorax 64(5):451–457. doi:10.1136/thx.2008.105437

    Article  CAS  PubMed  Google Scholar 

  32. Reijntjes S, Zile MH, Maden M (2010) The expression of Stra6 and Rdh10 in the avian embryo and their contribution to the generation of retinoid signatures. Int J Dev Biol 54(8–9):1267–1275. doi:10.1387/ijdb.093009sr

    Article  CAS  PubMed  Google Scholar 

  33. Tsukui T, Capdevila J, Tamura K, Ruiz-Lozano P, Rodriguez-Esteban C, Yonei-Tamura S, Magallón J, Chandraratna RA, Chien K, Blumberg B, Evans RM, Belmonte JC (1999) Multiple left-right asymmetry defects in Shh(−/−) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1. Proc Natl Acad Sci USA 96(20):11376–11381. doi:10.1073/pnas.96.20.11376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sánchez-Guardado LO, Ferran JL, Mijares J, Puelles L, Rodríguez-Gallardo L, Hidalgo-Sánchez M (2009) Raldh3 gene expression pattern in the developing chicken inner ear. J Comp Neurol 514(1):49–65. doi:10.1002/cne.21984

    Article  PubMed  Google Scholar 

  35. Michaille JJ, Kanzler B, Blanchet S, Garnier JM, Dhouailly D (1995) Characterization of cDNAs encoding two chick retinoic acid receptor alpha isoforms and distribution of retinoic acid receptor alpha, beta and gamma transcripts during chick skin development. Int J Dev Biol 39(4):587–596

    CAS  PubMed  Google Scholar 

  36. Bayha E, Jørgensen MC, Serup P, Grapin-Botton A (2009) Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis. PLoS One 4(6):e5845. doi:10.1371/journal.pone.0005845

    Article  PubMed  PubMed Central  Google Scholar 

  37. Heine P, Dohle E, Bumsted-O’Brien K, Engelkamp D, Schulte D (2008) Evidence for an evolutionary conserved role of homothorax/Meis1/2 during vertebrate retina development. Development 135(5):805–811. doi:10.1242/dev.012088

    Article  CAS  PubMed  Google Scholar 

  38. Gouveia A, Marcelino HM, Gonçalves L, Palmeirim I, Andrade RP (2015) Patterning in time and space: hoxB cluster gene expression in the developing chick embryo. Cell Cycle 14(1):135–145. doi:10.4161/15384101.2014.972868

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yamagishi T, Ando K, Nakamura H, Nakajima Y (2012) Expression of the Tgfβ2 gene during chick embryogenesis. Anat Rec (Hoboken) 295(2):257–267. doi:10.1002/ar.22400

    Article  Google Scholar 

  40. Dady A, Blavet C, Duband JL (2012) Timing and kinetics of E- to N-cadherin switch during neurulation in the avian embryo. Dev Dyn 241(8):1333–1349. doi:10.1002/dvdy.23813

    Article  CAS  PubMed  Google Scholar 

  41. Domowicz MS, Henry JG, Wadlington N, Navarro A, Kraig RP, Schwartz NB (2011) Astrocyte precursor response to embryonic brain injury. Brain Res 1389:35–49. doi:10.1016/j.brainres.2011.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nakazawa F, Nagai H, Shin M, Sheng G (2006) Negative regulation of primitive hematopoiesis by the FGF signaling pathway. Blood 108(10):3335–3343. doi:10.1182/blood-2006-05-021386

    Article  CAS  PubMed  Google Scholar 

  43. Riddle RD, Johnson RL, Laufer E, Tabin C (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75(7):1401–1416. doi:10.1016/0092-8674(93)90626-2

    Article  CAS  PubMed  Google Scholar 

  44. Lorda-Diez CI, Torre-Pérez N, García-Porrero JA, Hurle JM, Montero JA (2009) Expression of Id2 in the developing limb is associated with zones of active BMP signaling and marks the regions of growth and differentiation of the developing digits. Int J Dev Biol 53(8–10):1495–1502. doi:10.1387/ijdb.072415cl

    Article  CAS  PubMed  Google Scholar 

  45. Henrique D, Adam J, Myat A, Chitnis A, Lewis J, Ish-Horowicz D (1995) Expression of a Delta homologue in prospective neurons in the chick. Nature 375:787–790. doi:10.1038/375787a0

    Article  CAS  PubMed  Google Scholar 

  46. Zachman RD (1995) Role of vitamin A in lung development. J Nutr 125(6 Suppl):1634S–1638S

    CAS  PubMed  Google Scholar 

  47. Swarr DT, Morrisey EE (2015) Lung endoderm morphogenesis: gasping for form and function. Annu Rev Cell Dev Biol 31:553–573. doi:10.1146/annurev-cellbio-100814-125249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fex G, Johannesson G (1988) Retinol transfer across and between phospholipid bilayer membranes. Biochim Biophys Acta 944(2):249–255. doi:10.1016/0005-2736(88)90438-5

    Article  CAS  PubMed  Google Scholar 

  49. Bouillet P, Sapin V, Chazaud C, Messaddeq N, Décimo D, Dollé P, Chambon P (1997) Developmental expression pattern of Stra6, a retinoic acid-responsive gene encoding a new type of membrane protein. Mech Dev 63(2):173–186. doi:10.1016/S0925-4773(97)00039-7

    Article  CAS  PubMed  Google Scholar 

  50. Golzio C, Martinovic-Bouriel J, Thomas S, Mougou-Zrelli S, Grattagliano-Bessieres B, Bonniere M, Delahaye S, Munnich A, Encha-Razavi F, Lyonnet S, Vekemans M, Attie-Bitach T, Etchevers HC (2007) Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6. Am J Hum Genet 80(6):1179–1187. doi:10.1086/518177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick DR, Nürnberg G, Brasch F, Schirmer-Zimmermann H, Tolmie JL, Chitayat D, Houge G, Fernández-Martínez L, Keating S, Mortier G, Hennekam RC, von der Wense A, Slavotinek A, Meinecke P, Bitoun P, Becker C, Nürnberg P, Reis A, Rauch A (2007) Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet 80(3):550–560. doi:10.1086/512203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Miura T, Hartmann D, Kinboshi M, Komada M, Ishibashi M, Shiota K (2009) The cyst-branch difference in developing chick lung results from a different morphogen diffusion coefficient. Mech Dev 126(3–4):160–172. doi:10.1016/j.mod.2008.11.006

    Article  CAS  PubMed  Google Scholar 

  53. Dupé V, Matt N, Garnier JM, Chambon P, Mark M, Ghyselinck NB (2003) A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. Proc Natl Acad Sci USA 100(24):14036–14041. doi:10.1073/pnas.2336223100

    Article  PubMed  PubMed Central  Google Scholar 

  54. Li E, Sucov HM, Lee KF, Evans RM, Jaenisch R (1993) Normal development and growth of mice carrying a targeted disruption of the alpha 1 retinoic acid receptor gene. Proc Natl Acad Sci USA 15(90):1590–1594

    Article  Google Scholar 

  55. Luo J, Pasceri P, Conlon RA, Rossant J, Giguère V (1995) Mice lacking all isoforms of retinoic acid receptor beta develop normally and are susceptible to the teratogenic effects of retinoic acid. Mech Dev 53(1):61–71. doi:10.1016/0925-4773(95)00424-6

    Article  CAS  PubMed  Google Scholar 

  56. Lohnes D, Mark M, Mendelsohn C, Dollé P, Dierich A, Gorry P, Gansmuller A, Chambon P (1994) Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 120(10):2723–2748

    CAS  PubMed  Google Scholar 

  57. Dollé P, Rubert E, Leroy P, Morriss-Kay G, Chambon P (1990) Retinoic acid receptors and cellular retinoid binding proteins I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development 110:1133–1151

    PubMed  Google Scholar 

  58. Mollard R, Ghyselinck NB, Wendling O, Chambon P, Mark M (2000) Stage-dependent responses of the developing lung to retinoic acid signaling. Int J Dev Biol 44(5):457–462

    CAS  PubMed  Google Scholar 

  59. Mollard R, Viville S, Ward SJ, Décimo D, Chambon P, Dollé P (2000) Tissue-specific expression of retinoic acid receptor isoform transcripts in the mouse embryo. Mech Dev 94(1–2):223–232. doi:10.1016/S0925-4773(00)00303-8

    Article  CAS  PubMed  Google Scholar 

  60. Mercader N, Leonardo E, Piedra ME, Martínez-A C, Ros MA, Torres M (2000) Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. Development 127(18):3961–3970

    CAS  PubMed  Google Scholar 

  61. Liu J, Tseu I, Wang J, Tanswell K, Post M (2000) Transforming growth factor beta2, but not beta1 and beta3, is critical for early rat lung branching. Dev Dyn 217(4):343–360. doi:10.1002/(SICI)1097-0177(200004)217:4<343:AID-DVDY2>3.0.CO;2-F

    Article  CAS  PubMed  Google Scholar 

  62. Gontan C, de Munck A, Vermeij M, Grosveld F, Tibboel D, Rottier R (2008) Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation. Dev Biol 317(1):296–309. doi:10.1016/j.ydbio.2008.02.035

    Article  CAS  PubMed  Google Scholar 

  63. Rockich BE, Hrycaj SM, Shih HP, Nagy MS, Ferguson MA, Kopp JL, Sander M, Wellik DM, Spence JR (2013) Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. Proc Natl Acad Sci USA 110(47):E4456–E4464. doi:10.1073/pnas.1311847110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kamachi Y, Kondoh H (2013) Sox proteins: regulators of cell fate specification and differentiation. Development 140(20):4129–4144. doi:10.1242/dev.091793

    Article  CAS  PubMed  Google Scholar 

  65. Zhu Y, Li Y, Jun Wei JW, Liu X (2012) The role of Sox genes in lung morphogenesis and cancer. Int J Mol Sci 13(12):15767–15783. doi:10.3390/ijms131215767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ishii Y, Rex M, Scotting PJ, Yasugi S (1998) Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial–mesenchymal interactions. Dev Dyn 213(4):464–475. doi:10.1002/(SICI)1097-0177(199812)213:4<464:AID-AJA11>3.0.CO;2-Z

    Article  CAS  PubMed  Google Scholar 

  67. Que J, Okubo T, Goldenring JR, Nam KT, Kurotani R, Morrisey EE, Taranova O, Pevny LH, Hogan BL (2007) Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development 134(13):2521–2531. doi:10.1242/dev.003855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Que J, Luo X, Schwartz RJ, Hogan BL (2009) Multiple roles for Sox2 in the developing and adult mouse trachea. Development 136(11):1899–1907. doi:10.1242/dev.034629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Tompkins DH, Besnard V, Lange AW, Keiser AR, Wert SE, Bruno MD, Whitsett JA (2011) Sox2 activates cell proliferation and differentiation in the respiratory epithelium. Am J Respir Cell Mol Biol 45(1):101–110. doi:10.1165/rcmb.2010-0149OC

    Article  CAS  PubMed  Google Scholar 

  70. Liu Y, Hogan BL (2002) Differential gene expression in the distal tip endoderm of the embryonic mouse lung. Gene Expr Patterns 2(3–4):229–233. doi:10.1016/S1567-133X(02)00057-1

    Article  CAS  PubMed  Google Scholar 

  71. Turcatel G, Rubin N, Menke DB, Martin G, Shi W, Warburton D (2013) Lung mesenchymal expression of Sox9 plays a critical role in tracheal development. BMC Biol 11:117. doi:10.1186/1741-7007-11-117

    Article  PubMed  PubMed Central  Google Scholar 

  72. Park J, Zhang JJ, Moro A, Kushida M, Wegner M, Kim PC (2010) Regulation of Sox9 by Sonic Hedgehog (Shh) is essential for patterning and formation of tracheal cartilage. Dev Dyn 239(2):514–526. doi:10.1002/dvdy.22192

    Article  CAS  PubMed  Google Scholar 

  73. Turcatel G, Millette K, Thornton M, Leguizamon S, Grubbs B, Shi W, Warburton D (2017) Cartilage rings contribute to the proper embryonic tracheal epithelial differentiation, metabolism, and expression of inflammatory genes. Am J Physiol Lung Cell Mol Physiol 312(2):L196–L207. doi:10.1152/ajplung.00127.2016

    Article  PubMed  Google Scholar 

  74. Rawlins EL, Clark CP, Xue Y, Hogan BL (2009) The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136(22):3741–3745. doi:10.1242/dev.037317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Marklund M, Sjödal M, Beehler BC, Jessell TM, Edlund T, Gunhaga L (2004) Retinoic acid signalling specifies intermediate character in the developing telencephalon. Development 131(17):4323–4332. doi:10.1242/dev.01308

    Article  CAS  PubMed  Google Scholar 

  76. Capdevila J, Tsukui T, Rodríquez Esteban C, Zappavigna V, Izpisúa Belmonte JC (1999) Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin. Mol Cell 4(5):839–849. doi:10.1016/S1097-2765(00)80393-7

    Article  CAS  PubMed  Google Scholar 

  77. Pelton RW, Dickinson ME, Moses HL, Hogan BL (1990) In situ hybridization analysis of TGF beta 3 RNA expression during mouse development: comparative studies with TGF beta 1 and beta 2. Development 110(2):609–620

    CAS  PubMed  Google Scholar 

  78. Bragg AD, Moses HL, Serra R (2001) Signaling to the epithelium is not sufficient to mediate all of the effects of transforming growth factor beta and bone morphogenetic protein 4 on murine embryonic lung development. Mech Dev 109(1):13–26. doi:10.1016/S0925-4773(01)00508-1

    Article  CAS  PubMed  Google Scholar 

  79. Tang XH, Gudas LJ (2011) Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol 6:345–364. doi:10.1146/annurev-pathol-011110-130303

    Article  CAS  PubMed  Google Scholar 

  80. Maden M (2004) Retinoids in lung development and regeneration. Curr Topics Dev Biol 61:153–189. doi:10.1016/S0070-2153(04)61007-6

    Article  CAS  Google Scholar 

  81. Cardoso WV, Williams MC, Mitsialis SA, Joyce-Brady M, Rishi AK, Brody JS (1995) Retinoic acid induces changes in the pattern of airway branching and alters epithelial cell differentiation in the developing lung in vitro. Am J Respir Cell Mol Biol 12(5):464–476. doi:10.1165/ajrcmb.12.5.7742011

    Article  CAS  PubMed  Google Scholar 

  82. Pereira-Terra P, Moura RS, Nogueira-Silva C, Correia-Pinto J (2015) Neuroendocrine factors regulate retinoic acid receptors in normal and hypoplastic lung development. J Physiol 593(15):3301–3311. doi:10.1113/JP270477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Schuger L, Varani J, Mitra R Jr, Gilbride K (1993) Retinoic acid stimulates mouse lung development by a mechanism involving epithelial–mesenchymal interaction and regulation of epidermal growth factor receptors. Dev Biol 159(2):462–473. doi:10.1006/dbio.1993.1256

    Article  CAS  PubMed  Google Scholar 

  84. Packer AI, Mailutha KG, Ambrozewicz LA, Wolgemuth DJ (2000) Regulation of the Hoxa4 and Hoxa5 genes in the embryonic mouse lung by retinoic acid and TGFbeta1: implications for lung development and patterning. Dev Dyn 217(1):62–74. doi:10.1002/(SICI)1097-0177(200001)217:1<62:AID-DVDY6>3.0.CO;2-U

    Article  CAS  PubMed  Google Scholar 

  85. Volpe MV, Vosatka RJ, Nielsen HC (2000) Hoxb-5 control of early airway formation during branching morphogenesis in the developing mouse lung. Biochim Biophys Acta 1475(3):337–345. doi:10.1016/S0304-4165(00)00087-8

    Article  CAS  PubMed  Google Scholar 

  86. Chang DR, Martinez Alanis D, Miller RK, Ji H, Akiyama H, McCrea PD, Chen J (2013) Lung epithelial branching program antagonizes alveolar differentiation. Proc Natl Acad Sci USA 110(45):18042–18051. doi:10.1073/pnas.1311760110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bürglin TR, Affolter M (2016) Homeodomain proteins: an update. Chromosoma 125(3):497–521. doi:10.1007/s00412-015-0543-8

    Article  PubMed  Google Scholar 

  88. Wellik DM (2007) Hox patterning of the vertebrate axial skeleton. Dev Dyn 236(9):2454–2463. doi:10.1002/dvdy.21286

    Article  CAS  PubMed  Google Scholar 

  89. Sakiyama J, Yokouchi Y, Kuroiwa A (2000) Coordinated expression of Hoxb genes and signaling molecules during development of the chick respiratory tract. Dev Biol 227(1):12–27. doi:10.1006/dbio.2000.9880

    Article  CAS  PubMed  Google Scholar 

  90. Cardoso WV, Mitsialis SA, Brody JS, Williams MC (1996) Retinoic acid alters the expression of pattern-related genes in the developing rat lung. Dev Dyn 207(1):47–59. doi:10.1002/(SICI)1097-0177(199609)207:1<47:AID-AJA6>3.0.CO;2-W

    Article  CAS  PubMed  Google Scholar 

  91. Volpe MV, Ramadurai SM, Pham LD, Nielsen HC (2007) Hoxb-5 down regulation alters Tenascin-C, FGF10 and Hoxb gene expression patterns in pseudoglandular period fetal mouse lung. Front Biosci 12:860–873. doi:10.2741/2108

    Article  CAS  PubMed  Google Scholar 

  92. Chen F, Desai TJ, Qian J, Niederreither K, Lü J, Cardoso WV (2007) Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction. Development 134(16):2969–2979. doi:10.1242/dev.006221

    Article  CAS  PubMed  Google Scholar 

  93. Chen H, Zhuang F, Liu YH, Xu B, Del Moral P, Deng W, Chai Y, Kolb M, Gauldie J, Warburton D, Moses HL, Shi W (2008) TGF-beta receptor II in epithelia versus mesenchyme plays distinct roles in the developing lung. Eur Respir J 32(2):285–295. doi:10.1183/09031936.00165407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J (1995) Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial–mesenchymal interaction. Nat Genet 11(4):415–421. doi:10.1038/ng1295-415

    Article  CAS  PubMed  Google Scholar 

  95. Serra R, Pelton RW, Moses HL (1994) TGF beta 1 inhibits branching morphogenesis and N-myc expression in lung bud organ cultures. Development 120(8):2153–2161

    CAS  PubMed  Google Scholar 

  96. Zhao J, Bu D, Lee M, Slavkin HC, Hall FL, Warburton D (1996) Abrogation of transforming growth factor-beta type II receptor stimulates embryonic mouse lung branching morphogenesis in culture. Dev Biol 180(1):242–257. doi:10.1006/dbio.1996.0298

    Article  CAS  PubMed  Google Scholar 

  97. Roschger C, Cabrele C (2017) The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal 15(1):7. doi:10.1186/s12964-016-0161-y

    Article  PubMed  PubMed Central  Google Scholar 

  98. Sekine K, Ohuchi H, Fujiwara M, Yamasaki M, Yoshizawa T, Sato T, Yagishita N, Matsui D, Koga Y, Itoh N, Kato S (1999) Fgf10 is essential for limb and lung formation. Nat Genet 21(1):138–141. doi:10.1038/5096

    Article  CAS  PubMed  Google Scholar 

  99. Bellusci S, Grindley J, Emoto H, Itoh N, Hogan BL (1997) Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 124(23):4867–4878

    CAS  PubMed  Google Scholar 

  100. Fernandes-Silva H, Correia-Pinto J, Moura RS (2017) Canonical sonic hedgehog signaling in early lung development. J Dev Biol 5(1):3. doi:10.3390/jdb5010003

    Article  Google Scholar 

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Acknowledgements

The authors would like to thank Ana Lima for slide sectioning and Rita Lopes for contributing to the initiation of this project. This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the Project POCI-01-0145-FEDER-007038; and by the Project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal

    Hugo Fernandes-Silva, Patrícia Vaz-Cunha, Violina Baranauskaite Barbosa, Carla Silva-Gonçalves, Jorge Correia-Pinto & Rute Silva Moura

  2. ICVS/3B’s, PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal

    Hugo Fernandes-Silva, Patrícia Vaz-Cunha, Violina Baranauskaite Barbosa, Carla Silva-Gonçalves, Jorge Correia-Pinto & Rute Silva Moura

  3. Department of Pediatric Surgery, Hospital de Braga, 4710-243, Braga, Portugal

    Jorge Correia-Pinto

  4. Biology Department, School of Sciences, University of Minho, 4710-057, Braga, Portugal

    Rute Silva Moura

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  1. Hugo Fernandes-Silva
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18_2017_2600_MOESM1_ESM.tif

Fig. S1 Hematoxylin and eosin staining of slide sections corresponding to stra6 (a), raldh2 (b), cyp26a1 (c), rarα (d) and rarβ (e) represented in Fig. 1. Scale bar: 100 µm. (TIFF 9236 kb)

18_2017_2600_MOESM2_ESM.tif

Fig. S2 Hematoxylin and eosin staining of slide sections corresponding to sox2 (a), sox9 (b), meis1 (c), meis2 (d) and tgfβ2 (e) represented in Fig. 2. Scale bar: 100 µm. (TIFF 9228 kb)

18_2017_2600_MOESM3_ESM.tif

Fig. S3 l-cam expression pattern at early stages of chick lung development. Representative examples of in situ hybridization of stage b1, b2 and b3 lungs for l-cam (a-d), n ≥ 6 per stage. l-cam is exclusively expressed in the pulmonary epithelium (b, d: black arrow) and the secondary bronchi (c, d: asterisk). Scale bar: whole mount, 500 µm; slide section, 100 µm. The black rectangle in image c indicate the region shown in corresponding slide section. (TIFF 3926 kb)

18_2017_2600_MOESM4_ESM.tif

Fig. S4 id2 expression pattern at early stages of chick lung development. Representative examples of in situ hybridization of stage b1, b2 and b3 lungs for id2 (a-d), n ≥ 6 per stage. id2 is present in the mesenchymal compartment, mainly in ventral region (b; open arrowhead) and, specifically, in the dorsal region surrounding the proximal-most bud (c; dashed arrow). Expression around the trachea (a; dark arrowhead) seems to be stage dependent. Epithelial expression seems to be restricted to the growing tips (b; asterisk). Slide sectioning revealed that id2 is absent from the epithelium of the main bronchi (d; black arrow), but it is expressed in the distal ends of secondary bronchi (d; asterisk). Dorsal mesenchyme was identified as mesothelium (d; section sign) in the slide sections. Scale bar: whole mount, 500 µm; slide section, 100 µm. The black rectangle in image c indicates the region shown in corresponding slide section. (TIFF 3972 kb)

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Fernandes-Silva, H., Vaz-Cunha, P., Barbosa, V.B. et al. Retinoic acid regulates avian lung branching through a molecular network. Cell. Mol. Life Sci. 74, 4599–4619 (2017). https://doi.org/10.1007/s00018-017-2600-3

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