A retinoic acid–dependent network in the foregut controls formation of the mouse lung primordium
Felicia Chen, … , Karen Niederreither, Wellington V. Cardoso
Felicia Chen, … , Karen Niederreither, Wellington V. Cardoso
Published May 17, 2010
Citation Information: J Clin Invest. 2010;120(6):2040-2048. https://doi.org/10.1172/JCI40253.
View: Text | PDF
Research Article Development

A retinoic acid–dependent network in the foregut controls formation of the mouse lung primordium

Abstract

The developmental abnormalities associated with disruption of signaling by retinoic acid (RA), the biologically active form of vitamin A, have been known for decades from studies in animal models and humans. These include defects in the respiratory system, such as lung hypoplasia and agenesis. However, the molecular events controlled by RA that lead to formation of the lung primordium from the primitive foregut remain unclear. Here, we present evidence that endogenous RA acts as a major regulatory signal integrating Wnt and Tgfβ pathways in the control of Fgf10 expression during induction of the mouse primordial lung. We demonstrated that activation of Wnt signaling required for lung formation was dependent on local repression of its antagonist, Dickkopf homolog 1 (Dkk1), by endogenous RA. Moreover, we showed that simultaneously activating Wnt and repressing Tgfβ allowed induction of both lung buds in RA-deficient foreguts. The data in this study suggest that disruption of Wnt/Tgfβ/Fgf10 interactions represents the molecular basis for the classically reported failure to form lung buds in vitamin A deficiency.

Authors

Felicia Chen, Yuxia Cao, Jun Qian, Fengzhi Shao, Karen Niederreither, Wellington V. Cardoso

×

Figure 1

Dkk1 is a target of RA at the onset of lung morphogenesis.

Options: View larger image (or click on image) Download as PowerPoint
Dkk1 is a target of RA at the onset of lung morphogenesis. (A) Real...
(A) Real-time PCR. Dkk1 upregulation in RA-deficient foreguts (BMS-treated WT and unrescued Raldh2–/–) compared with respective controls (Ctr). (B and C) Dkk1 ISH in WT and Raldh2–/– embryos (12S, top) coimmunostained with Sox2 (bottom), depicting (B) no Dkk1 signals in the foregut (Fg, boxed regions) of WT embryo and (C) strong Dkk1 (blue arrowheads) in both endoderm (red arrowheads, Sox2-labeled brown nuclei) and mesoderm of Raldh2–/– embryo. Original magnification, ×10 (top); ×100 (bottom). (D–I) Reciprocal pattern of Dkk1 expression (D–F, WMISH) and RARElacZ activity (G–I) in the foregut, head, and tail (arrows) in RA-sufficient (D and G, 16S–18S; E and H, 11S–12S), and RA-deficient (F and I, 11S–12S) embryos. (J–M) WMISH of Dkk1 in 24-hour cultured foreguts revealed increased signals in RA-deficient conditions in which the lung failed to form (K and M, asterisks). Below, diagrams depict morphology of each condition after 72 hours. Ht, heart; Lu, lung; St, stomach; Th, thyroid. Scale bar: 450 μm (D–I); 300 μm (J–M).