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Published on: April 11, 2025
Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis
Tushar J Desai1, Felicia Chen, Jining Lü
1Pulmonary Center, Boston University School of Medicine, 80 East Concord Street R-304, Boston, MA 02118, USA.
Abstract:
Retinoic acid (RA) signaling is required for normal development of multiple organs. However, little is known about how RA influences the initial stages of lung development. Here, we used a combination of genetic, pharmacological and explant culture approaches to address this issue, and to investigate how signaling by different RA receptors (RAR) mediates the RA effects. We analyzed initiation of lung development in retinaldehyde dehydrogenase-2 (Raldh2) null mice, a model in which RA signaling is absent from the foregut from its earliest developmental stages. We provide evidence that RA is dispensable for specification of lung cell fate in the endoderm. By using synthetic retinoids to selectively activate RAR alpha or beta signaling in this model, we demonstrate novel and unique functions of these receptors in the early lung. We show that activation of RAR beta, but not alpha, induces expression of the fibroblast growth factor Fgf10 and bud morphogenesis in the lung field. Similar analysis of wild type foregut shows that endogenous RAR alpha activity is required to maintain overall RA signaling, and to refine the RAR beta effects in the lung field. Our data support the idea that balanced activation of RAR alpha and beta is critical for proper lung bud initiation and endodermal differentiation.
Insights
Retinoic acid (RA) is not essential for initial lung cell fate but is crucial for proper lung bud formation. Balanced signaling through retinoic acid receptors (RAR) alpha and beta is critical for early lung development.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Retinoic acid (RA) signaling is vital for organ development, yet its role in early lung development remains unclear.
- Understanding how different retinoic acid receptors (RARs) mediate RA effects is crucial for comprehending lung organogenesis.
Purpose of the Study:
- To investigate the influence of RA on the initial stages of lung development.
- To elucidate the specific roles of RAR alpha and RAR beta in mediating RA's effects on lung initiation.
Main Methods:
- Utilized genetic (Raldh2 null mice), pharmacological (synthetic retinoids), and explant culture techniques.
- Analyzed lung development initiation in mice lacking RA signaling from the earliest foregut stages.
- Investigated the effects of selective RAR alpha and RAR beta activation.
Main Results:
- RA is dispensable for lung cell fate specification in the endoderm.
- Activation of RAR beta, but not RAR alpha, induces fibroblast growth factor Fgf10 and lung bud morphogenesis.
- Endogenous RAR alpha activity is required for maintaining RA signaling and refining RAR beta-mediated effects.
Conclusions:
- Balanced activation of RAR alpha and RAR beta is critical for proper lung bud initiation.
- Specific RARs play distinct and complementary roles in early lung development and endodermal differentiation.
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