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.
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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

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Figure 5

Wnt rescues lung agenesis in Dkk1-treated and RA-deficient foreguts.

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Wnt rescues lung agenesis in Dkk1-treated and RA-deficient foreguts. (A–...
(A–D) Engraftment of beads soaked in Wnt3a, but not PBS, rescued lung buds bilaterally in Dkk1-treated foreguts (A–C), as confirmed by strong Nkx2-1 expression (arrowheads). Bilateral rescue was also observed when Gsk3b inhibitor was added to Dkk1-treated foreguts (D). (E and F) Exogenous FGF10 (F10) beads induced buds expressing Nkx2-1 (arrows) in Dkk1-treated foreguts (E), a response similarly elicited in BMS-treated foreguts (F). (G–P) Engraftment of Wnt3a beads onto BMS-treated foreguts induced only 1 lung bud, labeled by Nkx2-1 (G and H, arrowheads), although BATgal activity (I) and Fgf10 expression (J) were clearly present on both sides of the lung endoderm (arrows). Similar phenotypes were seen in foreguts treated simultaneously with BMS and Gsk3b inhibitor (K–N) and in Raldh2–/– foreguts treated with Wnt3a beads (O–P). Red asterisks indicate sites of unilateral bud agenesis. Original magnification, ×10 (A, B, D–G, I–K, and M–P); ×20 (C, H, and L).