Cellular and Molecular Life Sciences

, Volume 74, Issue 24, pp 4599–4619 | Cite as

Retinoic acid regulates avian lung branching through a molecular network

  • Hugo Fernandes-Silva
  • Patrícia Vaz-Cunha
  • Violina Baranauskaite Barbosa
  • Carla Silva-Gonçalves
  • Jorge Correia-Pinto
  • Rute Silva Moura
Original Article


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.


Chick lung Pulmonary development Branching morphogenesis Signaling pathways sox2 sox9 



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.

Supplementary material

18_2017_2600_MOESM1_ESM.tif (9 mb)
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 (9 mb)
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 (3.8 mb)
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 (3.9 mb)
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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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Hugo Fernandes-Silva
    • 1
    • 2
  • Patrícia Vaz-Cunha
    • 1
    • 2
  • Violina Baranauskaite Barbosa
    • 1
    • 2
  • Carla Silva-Gonçalves
    • 1
    • 2
  • Jorge Correia-Pinto
    • 1
    • 2
    • 3
  • Rute Silva Moura
    • 1
    • 2
    • 4
  1. 1.Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
  2. 2.ICVS/3B’s, PT Government Associate LaboratoryBraga/GuimarãesPortugal
  3. 3.Department of Pediatric SurgeryHospital de BragaBragaPortugal
  4. 4.Biology Department, School of SciencesUniversity of MinhoBragaPortugal

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