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First published online 18 July 2007
doi: 10.1242/dev.006221

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Inhibition of Tgfß signaling by endogenous retinoic acid is essential for primary lung bud induction

¹ Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
² Biochemistry Department, Stanford University, Stanford, CA 94305, USA.
³ Baylor College of Medicine, Houston, TX 77030, USA.

^* Author for correspondence (e-mail: wcardoso{at}bu.edu)

Accepted 17 June 2007

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 Tgfß targets. Increased Smad2 phosphorylation further suggested that Tgfß 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 Tgfß targets in Raldh2-null foreguts. Interestingly, the lung defect that resulted from RA-deficiency could be reproduced in RA-sufficient foreguts by hyperactivating Tgfß signaling with exogenous TGFß1. Preventing activation of endogenous Tgfß signaling with a pan-specific TGFß-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-Tgfß-Fgf10 interactions in the developing foregut, in which endogenous RA controls Tgfß activity in the prospective lung field to allow local expression of Fgf10 and induction of lung buds.

Key words: Retinoic acid, Fgf10, Fibroblast growth factor, Tgfß, Transforming growth factor, Lung development, Foregut development, Organogenesis, Mouse, Raldh2 (Aldh1a2)

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