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.

Dietary vitamin A intake below the recommended daily intake during pregnancy and the risk of congenital diaphragmatic hernia in the offspring

“…However, a detailed epidemiologic study has not been performed and most of these countries lack registries of birth defects. In addition, it is well known that vitamin A and its metabolite retinoic acid have a crucial role in animal lung development (Chen et al, 2010), which is disturbed in patients with CDH. Further, maternal vitamin A repletion in a vitamin A deficient population improves lung function in the offspring (Checkley et al, 2010).…”

The building blocks of mammalian lung development

“…Wnt signaling has also been implicated in proximal-distal epithelial patterning and differentiation during lung development and the roles of other Wnt ligands remain obscure (Shu et al, 2005;Zhang et al, 2008). Interestingly, Wnt signaling is also absolutely required for the initial specification of the respiratory epithelial lineage from the foregut endoderm (Goss et al, 2009;Harris-Johnson et al, 2009;Chen et al, 2010).…”

Gpr177 regulates pulmonary vasculature development

“…Previous studies have shown that epithelial signaling molecules, including sonic hedgehog and vascular endothelial growth factors (VEGFs), regulate the proliferation and differentiation of mesenchymal cells (Healy et al, 2000;Miller et al, 2004;Del Moral et al, 2006;White et al, 2006;Chen et al, 2010). However, recent studies regarding the role of epithelial Wnts in vasculature development generate inconsistent conclusions (Shu et al, 2002;Rajagopal et al, 2008).…”