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INHIBITION OF TGF BETA SIGNALING BY ENDOGENOUS RETINOIC ACID IS ESSENTIAL FOR PRIMARY LUNG BUD INDUCTION
Author(s) -
Cardoso Wellington V.,
Desai Tushar,
Qian Jun,
Niederreither Karen,
Lu Jining,
Chen Felicia
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a199-b
Subject(s) - retinoic acid , biology , fgf10 , transforming growth factor , downregulation and upregulation , signal transduction , endocrinology , medicine , transforming growth factor beta , lung , cancer research , microbiology and biotechnology , fibroblast growth factor , receptor , cell culture , genetics , gene
Disruption of retinoic acid (RA) signaling during early development results in severe respiratory tract abnormalities, including lung agenesis. Previous studies suggest that this may 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 foregut that may be critical for lung formation. By performing global gene expression analysis of RA deficient foreguts from a genetic (Raldh2−/− retinaldehyde dehydrogenase–2) and a pharmacological (BMS493) mouse model, we found upregulation of a large number of Tgf(targets. Increased Smad2 phosphorylation further suggested that Tgf(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(targets in Raldh2 null foreguts. Interestingly, the lung defect that resulted from RA‐deficiency could be reproduced in RA‐sufficient foreguts by hyperactivating Tgf(signaling with exogenous TGF(1. Preventing activation of endogenous Tgf(signaling with a pan‐specific TGF(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(‐Fgf10 interactions in the developing foregut, in which endogenous RA tightly controls TGF(levels in the prospective lung field to allow local expression of Fgf10 and induction of lung buds