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Development ePress online publication date 18 Jul 2007
doi: 10.1242/dev.006221

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Research article

Inhibition of Tgf{beta} signaling by endogenous retinoic acid is essential for primary lung bud induction


Felicia Chen, Tushar J. Desai, Jun Qian, Karen Niederreither, Jining Lü, and Wellington V. Cardoso*
* Author for correspondence (e-mail: wcardoso{at}bu.edu)

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 Tgf{beta} targets. Increased Smad2 phosphorylation further suggested that Tgf{beta} 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 Tgf{beta} targets in Raldh2-null foreguts. Interestingly, the lung defect that resulted from RA-deficiency could be reproduced in RA-sufficient foreguts by hyperactivating Tgf{beta} signaling with exogenous TGF{beta}1. Preventing activation of endogenous Tgf{beta} signaling with a pan-specific TGF{beta}-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-Tgf{beta}-Fgf10 interactions in the developing foregut, in which endogenous RA controls Tgf{beta} activity in the prospective lung field to allow local expression of Fgf10 and induction of lung buds.


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