A Retinoic Acid-Hedgehog Cascade Coordinates Mesoderm-Inducing Signals and Endoderm Competence during Lung Specification.
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.
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Scott A
SA
Rankin
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Lu
L
Han
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Kyle W
KW
McCracken
Division of Neonatology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Alan P
AP
Kenny
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Christopher T
CT
Anglin
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Emily A
EA
Grigg
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Calyn M
CM
Crawford
Division of Developmental Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
James M
JM
Wells
Division of Pulmonary Biology, Department of Pediatrics, Perinatal Institute and Cincinnati Children's Hospital, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
John M
JM
Shannon
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.
Aaron M
AM
Zorn
D000818:Animals; D019521:Body Patterning; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004707:Endoderm / Q000196:embryology* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007422:Intestines / Q000196:embryology; D008024:Ligands; D008168:Lung / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D012119:Respiration; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D029867:Xenopus Proteins / Q000378:metabolism; D014982:Xenopus laevis
D053823:Hedgehog Proteins; D008024:Ligands; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014212:Tretinoin
Bmp; Hedgehog; Nkx2-1; Wnt; Xenopus; lung development; organogenesis; retinoic acid