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Mouse Embryonic Lung Culture, A System to Evaluate the Molecular Mechanisms of Branching
Published on: June 30, 2010
A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium
Felicia Chen1, Yuxia Cao, Jun Qian
1Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
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 Tgfbeta 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 Tgfbeta allowed induction of both lung buds in RA-deficient foreguts. The data in this study suggest that disruption of Wnt/Tgfbeta/Fgf10 interactions represents the molecular basis for the classically reported failure to form lung buds in vitamin A deficiency.
Insights
Retinoic acid (RA) regulates lung formation by controlling gene expression through Wnt and Tgfbeta pathways. This study reveals how RA deficiency disrupts these crucial signaling interactions, leading to lung developmental defects.
Area of Science:
- Developmental biology
- Molecular biology
- Respiratory system development
Background:
- Retinoic acid (RA) is essential for embryonic development, and its deficiency causes respiratory abnormalities like lung hypoplasia.
- The precise molecular mechanisms by which RA controls early lung development remain largely unknown.
Purpose of the Study:
- To elucidate the molecular pathways regulated by endogenous retinoic acid (RA) during mouse lung primordium formation.
- To investigate the integration of Wnt and Tgfbeta signaling by RA in controlling Fgf10 expression during lung induction.
Main Methods:
- Utilized mouse models to study endogenous RA signaling during lung development.
- Investigated the roles of Wnt, Tgfbeta, and Fgf10 signaling pathways and their interactions.
- Examined the regulation of Dickkopf homolog 1 (Dkk1) by RA.
Main Results:
- Endogenous RA is a key regulator integrating Wnt and Tgfbeta pathways for Fgf10 expression in primordial lung development.
- RA-dependent repression of Dkk1 is necessary for Wnt signaling activation during lung formation.
- Simultaneous activation of Wnt and repression of Tgfbeta can induce lung buds in RA-deficient conditions.
Conclusions:
- Disruption of Wnt/Tgfbeta/Fgf10 signaling interactions underlies lung bud formation failure in vitamin A deficiency.
- RA plays a critical role in orchestrating key signaling pathways essential for normal lung development.
