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Cell Rep 2016 Jun 28;161:66-78. doi: 10.1016/j.celrep.2016.05.060.
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A Retinoic Acid-Hedgehog Cascade Coordinates Mesoderm-Inducing Signals and Endoderm Competence during Lung Specification.

Rankin SA , Han L , McCracken KW , Kenny AP , Anglin CT , Grigg EA , Crawford CM , Wells JM , Shannon JM , Zorn AM .

Organogenesis of the trachea and lungs requires a complex series of mesoderm-endoderm interactions mediated by WNT, BMP, retinoic acid (RA), and hedgehog (Hh), but how these pathways interact in a gene regulatory network is less clear. Using Xenopus embryology, mouse genetics, and human ES cell cultures, we identified a conserved signaling cascade that initiates respiratory lineage specification. We show that RA has multiple roles; first RA pre-patterns the lateral plate mesoderm and then it promotes Hh ligand expression in the foregut endoderm. Hh subsequently signals back to the pre-patterned mesoderm to promote expression of the lung-inducing ligands Wnt2/2b and Bmp4. Finally, RA regulates the competence of the endoderm to activate the Nkx2-1+ respiratory program in response to these mesodermal WNT and BMP signals. These data provide insights into early lung development and a paradigm for how mesenchymal signals are coordinated with epithelial competence during organogenesis.

PubMed ID: 27320915
PMC ID: PMC5314425
Article link: Cell Rep
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: aldh1a2 axin2 bmp2 bmp4 bmp7.1 bmp7.2 ccnd1 dhh fgf10 fgf7 foxa1 foxa2 foxf1 gata4 gata5 gata6 gli1 gli2 gli3 hand1 id4 ihh isl1 nkx2-1 nkx2-5 osr1 ptch1 ptch2 rab40b rara rarg rdh10 sag sftpc shh smad1 smo sox2 vim wnt2 wnt2b wnt8a wnt8b
GO keywords: lung development [+]
Antibodies: Aldh1a2 Ab1 Casp3 Ab3 Fn1 Ab1 Foxf1 Ab1 H3f3a Ab2 Nkx2-1 Ab3 Rdh10 Ab1 Smad1 Ab12 Sox2 Ab4 Tuba4b Ab4
Morpholinos: aldh1a2 MO1 gli2 MO1 gli3 MO1 rdh10 MO1

Disease Ontology terms: esophageal atresia/tracheoesophageal fistula
Phenotypes: Xla Wt + Cyclopamine (Fig S2 B) [+]

Article Images: [+] show captions
References [+] :
Bayha, Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis. 2009, Pubmed