Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction.
Disruption of retinoic acid (RA) signaling during early development results in severe respiratory tract abnormalities, including lung agenesis. Previous studies suggest that this might result from failure to selectively induce fibroblast growth factor 10 (Fgf10) in the prospective lung region of the foregut. Little is known about the RA-dependent pathways present in the foregut that may be crucial for lung formation. By performing global gene expression analysis of RA-deficient foreguts from a genetic [retinaldehyde dehydrogenase 2 (Raldh2)-null] and a pharmacological (BMS493-treated) mouse model, we found upregulation of a large number of Tgfbeta targets. Increased Smad2 phosphorylation further suggested that Tgfbeta signaling was hyperactive in these foreguts when lung agenesis was observed. RA rescue of the lung phenotype was associated with low levels of Smad2 phosphorylation and downregulation of Tgfbeta targets in Raldh2-null foreguts. Interestingly, the lung defect that resulted from RA-deficiency could be reproduced in RA-sufficient foreguts by hyperactivating Tgfbeta signaling with exogenous TGF beta 1. Preventing activation of endogenous Tgfbeta signaling with a pan-specific TGFbeta-blocking antibody allowed bud formation and gene expression in the lung field of both Raldh2-null and BMS493-treated foreguts. Our data support a novel mechanism of RA-Tgfbeta-Fgf10 interactions in the developing foregut, in which endogenous RA controls Tgfbeta activity in the prospective lung field to allow local expression of Fgf10 and induction of lung buds.
Chen
Felicia
F
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
Desai
Tushar J
TJ
Qian
Jun
J
Niederreither
Karen
K
Lü
Jining
J
Cardoso
Wellington V
WV
D000818:Animals; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006133:Growth Substances / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000196:embryology*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*; D000099222:betaIG-H3 Protein
D003094:Collagen; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D016326:Extracellular Matrix Proteins; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018168:Receptors, Retinoic Acid; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014212:Tretinoin; D000099222:betaIG-H3 Protein; C526318:CCN2 protein, mouse; C496464:Fgf10 protein, mouse