Wnt/beta-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung.
Branching morphogenesis in the lung serves as a model for the complex patterning that is reiterated in multiple organs throughout development. Beta-catenin and Wnt signaling mediate critical functions in cell fate specification and differentiation, but specific functions during branching morphogenesis have remained unclear. Here, we show that Wnt/beta-catenin signaling regulates proximal-distal differentiation of airway epithelium. Inhibition of Wnt/beta-catenin signaling, either by expression of Dkk1 or by tissue-specific deletion of beta-catenin, results in disruption of distal airway development and expansion of proximal airways. Wnt/beta-catenin functions upstream of BMP4, FGF signaling, and N-myc. Moreover, we show that beta-catenin and LEF/TCF activate the promoters of BMP4 and N-myc. Thus, Wnt/beta-catenin signaling is a critical upstream regulator of proximal-distal patterning in the lung, in part, through regulation of N-myc, BMP4, and FGF signaling.
Shu
Weiguo
W
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Guttentag
Susan
S
Wang
Zhishan
Z
Andl
Thomas
T
Ballard
Philip
P
Lu
Min Min
MM
Piccolo
Stefano
S
Birchmeier
Walter
W
Whitsett
Jeffrey A
JA
Millar
Sarah E
SE
Morrisey
Edward E
EE
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000502:physiology*; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008168:Lung / Q000166:cytology / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D051153:Wnt Proteins; D051176:beta Catenin
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D005346:Fibroblast Growth Factors; D011505:Protein-Tyrosine Kinases