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Development 2012 Aug 01;13916:3010-20. doi: 10.1242/dev.078220.
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Suppression of Bmp4 signaling by the zinc-finger repressors Osr1 and Osr2 is required for Wnt/β-catenin-mediated lung specification in Xenopus.

Rankin SA , Gallas AL , Neto A , Gómez-Skarmeta JL , Zorn AM .

Embryonic development of the respiratory system is regulated by a series of mesenchymal-epithelial interactions that are only partially understood. Mesenchymal FGF and Wnt2/Wnt2b signaling are implicated in specification of mammalian pulmonary progenitors from the ventral foregut endoderm, but their epistatic relationship and downstream targets are largely unknown. In addition, how wnt2 and wnt2b are regulated in the developing foregut mesenchyme is unknown. We show that the Odd-skipped-related (Osr) zinc-finger transcriptional repressors Osr1 and Osr2 are redundantly required for Xenopus lung specification in a molecular pathway linking foregut pattering by FGFs to Wnt-mediated lung specification and RA-regulated lung bud growth. FGF and RA signals are required for robust osr1 and osr2 expression in the foregut endoderm and surrounding lateral plate mesoderm (lpm) prior to respiratory specification. Depletion of both Osr1 and Osr2 (Osr1/Osr2) results in agenesis of the lungs, trachea and esophagus. The foregut lpm of Osr1/Osr2-depleted embryos fails to express wnt2, wnt2b and raldh2, and consequently Nkx2.1(+) progenitors are not specified. Our data suggest that Osr1/Osr2 normally repress bmp4 expression in the lpm, and that BMP signaling negatively regulates the wnt2b domain. These results significantly advance our understanding of early lung development and may impact strategies to differentiate respiratory tissue from stem cells.

PubMed ID: 22791896
PMC ID: PMC3403107
Article link: Development
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: aldh1a2 bmp4 ctnnb1 darmin dkk1 fgf10 fgf7 fn1 foxa1 foxf1 hand1 lhx1 msx1 nkx2-1 nodal1 nr1h5 osr1 osr2 oxsr1 pax8 pdx1 sftpc shh smad1 sox17a sox2 tbx2 tbxt tcf3 tcf7l1 tnni3 uqcc6 ventx1 ventx1.2 wnt2 wnt2b
GO keywords: lung development [+]
Antibodies: Casp3 Ab1 Fn1 Ab1 Nkx2-1 Ab1 Smad1 Ab5 Sox2 Ab1
Morpholinos: osr1 MO1 osr2 MO1 wnt2 MO1

Disease Ontology terms: esophageal atresia/tracheoesophageal fistula
Phenotypes: Xtr Wt + BIO (fig.4.e) [+]

Article Images: [+] show captions
References [+] :
Beenken, The FGF family: biology, pathophysiology and therapy. 2009, Pubmed