Abstract
Lung organogenesis is guided by epithelial–mesenchymal interactions that coordinate cellular events responsible for the formation of the respiratory system. Several signaling pathways have been implicated in this process; among them, sonic hedgehog (Shh) signaling has emerged as a crucial regulator of branching morphogenesis in the mammalian lung. Canonical Shh signaling requires the presence of patched (Ptch) and smoothened (Smo) transmembrane receptors in order to induce the activation of glioblastoma (Gli) zinc finger transcription factors that are the true effectors of the pathway. Signal transduction is finely regulated by Ptch1, Gli, and Hhip (hedgehog-interacting protein). The present work characterizes, for the first time, the expression pattern of shh, ptch1, smo, gli1, and hhip in early stages of the embryonic chick lung. In situ hybridization studies revealed that these genes are expressed in the same cellular compartments as their mammalian counterparts, although their proximo-distal distribution is slightly changed. Moreover, the molecular interactions between fibroblast growth factor (FGF) and Shh signaling pathway were assessed, in vitro, by grafting beads soaked in SU5402 (an FGF receptor inhibitor). In the chick lung, Shh signaling seems to have some features that are species specific since shh is not a downstream target of FGF signaling. Nonetheless and despite the observed differences, these findings suggest a role for Shh signaling in the epithelial–mesenchymal interactions that control chick lung morphogenesis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abler LL, Mansour SL, Sun X (2009) Conditional gene inactivation reveals roles for Fgf10 and Fgfr2 in establishing a normal pattern of epithelial branching in the mouse lung. Dev Dyn 238:1999–2013. doi:10.1002/dvdy.22032
Agarwala S, Aglyamova GV, Marma AK, Fallon JF, Ragsdale CW (2005) Differential susceptibility of midbrain and spinal cord patterning to floor plate defects in the talpid2 mutant. Dev Biol 288:206–220. doi:10.1016/j.ydbio.2005.09.034
Bai CB, Auerbach W, Lee JS, Stephen D, Joyner AL (2002) Gli2, but not gli1, is required for initial shh signaling and ectopic activation of the shh pathway. Development 129:4753–4761
Bellusci S, Furuta Y, Rush MG, Henderson R, Winnier G, Hogan BL (1997a) Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. Dev Camb 124:53–63
Bellusci S, Grindley J, Emoto H, Itoh N, Hogan BL (1997b) Fibroblast growth factor 10 (fgf10) and branching morphogenesis in the embryonic mouse lung. Development 124(23):4867–4878
Brennan D, Chen X, Cheng L, Mahoney M, Riobo NA (2012) Noncanonical hedgehog signaling. Vitam Horm 88:55–72. doi:10.1016/B978-0-12-394622-5.00003-1
Briscoe J, Thérond PP (2013) The mechanisms of hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14(7):416–429. doi:10.1038/nrm3598
Chuang PT, McMahon AP (1999) Vertebrate hedgehog signalling modulated by induction of a hedgehog-binding protein. Nature 397:617–621. doi:10.1038/17611
Chuang PT, Kawcak TN, McMahon AP (2003) 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. doi:10.1101/gad.1026303
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
Grindley JC, Bellusci S, Perkins D, Hogan BLM (1997) Evidence for the involvement of the Gli gene family in embryonic mouse lung development. Dev Biol 188:337–348. doi:10.1006/dbio.1997.8644
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
Herriges M, Morrisey EE (2014) Lung development: orchestrating the generation and regeneration of a complex organ. Development 141:502–513. doi:10.1242/dev.098186
Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087. doi:10.1101/gad.938601
Kimura J, Deutsch GH (2007) Key mechanisms of early lung development. Pediatr Dev Pathol 10:335–347. doi:10.2350/07-06-0290.1
Kugler MC, Joyner AL, Loomis CA, Munger JS (2015) Sonic hedgehog signaling in the lung—from development to disease. Am J Respir Cell Mol Biol 52:1–13. doi:10.1165/rcmb.2014-0132TR
Litingtung Y, Lei L, Westphal H, Chiang C (1998) Sonic hedgehog is essential to foregut development. Nat Genet 20:58–61. doi:10.1038/1717
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
Maina JN (2012) Comparative molecular developmental aspects of the mammalian and the avian lungs, and the insectan tracheal system by branching morphogenesis: recent advances and future directions. Front Zool. doi:10.1186/1742-9994-9-16
Marigo V, Tabin CJ (1996) Regulation of patched by sonic hedgehog in the developing neural tube. Proc Natl Acad Sci USA 93:9346–9351. doi:10.1073/pnas.93.18.9346
Marigo V, Scott MP, Johnson RL, Goodrich LV, Tabin CJ (1996) Conservation in hedgehog signaling: induction of a chicken patched homolog by Sonic hedgehog in the developing limb. Development 122:1225–1233
Miller LA, Wert SE, Whitsett JA (2001) Immunolocalization of sonic hedgehog (shh) in developing mouse lung. J Histochem Cytochem 49:1593–1604. doi:10.1177/002215540104901213
Miller LA, Wert SE, Clark JC, Xu Y, Perl AK, Whitsett JA (2004) Role of sonic hedgehog in patterning of tracheal–bronchial cartilage and the peripheral lung. Dev Dyn 231:57–71. doi:10.1002/dvdy.20105
Mohammadi M, McMahon G, Sun L, Tang C, Hirth P, Yeh BK, Hubbard SR, Schlessinger J (1997) Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 276(5314):955–960. doi:10.1126/science.276.5314.95
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:e17660. doi:10.1371/journal.pone.0017660
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:e112388. doi:10.1371/journal.pone.0112388
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
Nogueira-Silva C, Piairo P, Carvalho-Dias E, Veiga C, Moura RS, Correia-Pinto J (2013) The role of glycoprotein 130 family of cytokines in fetal rat lung development. PLoS ONE 8(6):e67607. doi:10.1371/journal.pone.0067607
Peixoto FO, Pereira-Terra P, Moura RS, Carvalho-Dias E, Correia-Pinto J, Nogueira-Silva C (2015) The role of ephrins-B1 and -B2 during fetal rat lung development. Cell Physiol Biochem 35(1):104–115. doi:10.1159/000369679
Pepicelli CV, Lewis PM, McMahon AP (1998) Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr Biol 8:1083–1086. doi:10.1016/S0960-9822(98)70446-4
Resende TP, Ferreira M, Teillet MA, Tavares AT, Andrade RP, Palmeirim I (2010) Sonic hedgehog in temporal control of somite formation. Proc Natl Acad Sci USA 107:12907–12912. doi:10.1073/pnas.1000979107
Riddle RD, Johnson RL, Laufer E, Tabin C (1993) Sonic hedgehog mediates the polarizing activity of ZPA. Cell 75:1401–1416. doi:10.1016/0092-8674(93)90626-2
Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H (1999) Regulation of gli2 and gli3 activities by an amino-terminal repression domain: implication of gli2 and gli3 as primary mediators of shh signaling. Development 126:3915–3924
Zhang M, Wang H, Teng H, Shi J, Zhang Y (2010) Expression of Shh signalling pathway components in the developing human lung. Histochem Cell Biol 134:327–335. doi:10.1007/s00418-010-0738-2
Acknowledgments
The authors would like to thank Ana Lima for slide sectioning and Sandra Fernandes for contributing to the initiation of this project. This project was funded by: project ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000017) co-funded by Programa Operacional Regional do Norte (ON.2- O Novo Norte), Quadro de Referência Estratégico Nacional (QREN), through Fundo Europeu de Desenvolvimento Regional (FEDER); FEDER funds through the Operational Programme Competitiveness Factors – COMPETE; National Funds through FCT - Foundation for Science and Technology under the project POCI-01-0145-FEDER-007038. RSM was supported by the ON.2 SR&TD Integrated Program (N-01-01-01-24-01-07), ref: UMINHO/BPD/31/2013. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Moura, R.S., Silva-Gonçalves, C., Vaz-Cunha, P. et al. Expression analysis of Shh signaling members in early stages of chick lung development. Histochem Cell Biol 146, 457–466 (2016). https://doi.org/10.1007/s00418-016-1448-1
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00418-016-1448-1