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Cell Rep. 2016 Jun 28;16(1):66-78. doi: 10.1016/j.celrep.2016.05.060. Epub 2016 Jun 16.

A Retinoic Acid-Hedgehog Cascade Coordinates Mesoderm-Inducing Signals and Endoderm Competence during Lung Specification.

Author information

1
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
2
Division of Neonatology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
3
Division of Pulmonary Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
4
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA. Electronic address: aaron.zorn@cchmc.org.

Abstract

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.

KEYWORDS:

Bmp; Hedgehog; Nkx2-1; Wnt; Xenopus; lung development; organogenesis; retinoic acid

PMID:
27320915
PMCID:
PMC5314425
DOI:
10.1016/j.celrep.2016.05.060
[Indexed for MEDLINE]
Free PMC Article

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