1. Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis
- Author
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Tushar J. Desai, Pierre Chambon, Felicia Chen, Jun Qian, Jining Lu, Wellington V. Cardoso, Pascal Dollé, Karen Niederreither, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I
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MESH: Aldehyde Oxidoreductases ,MESH: Signal Transduction ,Receptors, Retinoic Acid ,Organogenesis ,Retinoic acid ,Fibroblast growth factor ,MESH: Mice, Knockout ,Tissue Culture Techniques ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Morphogenesis ,MESH: Animals ,Receptor ,Lung ,Mice, Knockout ,0303 health sciences ,SftpC ,Retinoic Acid Receptor alpha ,Endoderm ,Foregut ,Cell Differentiation ,respiratory system ,Aldehyde Oxidoreductases ,Cell biology ,MESH: Endoderm ,Nkx2.1 ,embryonic structures ,Lung development ,Lung morphogenesis ,Signal Transduction ,MESH: Cell Differentiation ,Alpha (ethology) ,Biology ,Cell fate determination ,03 medical and health sciences ,Raldh2 ,Animals ,MESH: Lung ,MESH: Tissue Culture Techniques ,Molecular Biology ,MESH: Mice ,030304 developmental biology ,MESH: Receptors, Retinoic Acid ,FGF10 ,Fgf10 ,Endodermal specification ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Cell Biology ,MESH: Morphogenesis ,chemistry ,Immunology ,MESH: Fibroblast Growth Factor 10 ,Fibroblast Growth Factor 10 ,030217 neurology & neurosurgery ,RAR ,Developmental Biology - Abstract
International audience; 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.
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