Overexpression of Dominant Negative Retinoic Acid Receptor α Causes Alveolar Abnormality in Transgenic Neonatal Lungs

Li, Yang; Naltner, Angela; Yan, Cong

doi:10.1210/en.2002-0121

Cited by 39 publications

(26 citation statements)

References 17 publications

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“…In situ hybridization showed that the RAR mRNA was expressed in alveolar regions of the lung (31). Yang et al (32) showed that overexpression of a dominant negative RAR in the postnatal lung on days 1-21 after birth resulted in larger alveoli, fewer alveoli, fewer alveolar epithelial cells, and decreased alveolar surface area in the treated mice. These results suggest that RARs are required for postnatal alveolarization in the mouse lung.…”

Section: Discussionmentioning

confidence: 99%

Alveolarization in Retinoic Acid Receptor-β–Deficient Mice

et al. 2005

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Retinoids bind to nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors]. RAR␤, one of three isoforms of RARs (␣, ␤, and ␥), is expressed in the fetal and adult lung. We hypothesized that RAR␤ plays a role in alveolarization. Using morphometric analysis, we determined that there was a significant increase in the volume density of airspace in the alveolar region of the lung at 28, 42, and 56 d postnatal age in RAR␤ null mice when compared with wild-type controls. The mean cord length of the respiratory airspaces was increased in RAR␤ null animals at 42 d postnatal age. Respiratory gasexchange surface area per unit lung volume was significantly decreased in RAR␤ null animals at 28, 42, and 56 d postnatal age. In addition, alveolar ducts tended to comprise a greater proportion of the lung airspaces in the RAR␤ null mice. The RAR␤ null mice also had impaired respiratory function when compared with wild-type control mice. There was no effect of RAR␤ gene deletion on lung platelet-derived growth factor (PDGF) receptor ␣ mRNA levels in postnatal lung tissue at several postnatal ages. However PDGF-A protein levels were significantly lower in the RAR␤ null mice than in wild-type controls. Thus, deletion of the RAR␤ gene impairs the formation of the distal airspaces during the postnatal phase of lung maturation in mice via a pathway that may involve PDGF-A. Retinoids regulate the development of the conducting airways and the gas-exchange portion of the lung (1). The major biologically active retinoid, all-trans retinoic acid, is a metabolite of retinol (vitamin A) (2). Retinol can be stored within lung tissue esterified to fatty acids, where it can be released by retinyl ester hydrolases and then be converted to all-trans retinoic acid (1). All-trans retinoic acid binds with high affinity to retinoic acid receptors (RARs), which exist in three isoforms, ␣, ␤, and ␥ (3). Retinoid X receptors (RXRs) primarily bind 9-cis retinoic acid (3). RARs form a heterodimer with RXRs and bind to retinoid responsive elements in target genes (3). RARs and RXRs are members of the steroid hormone receptor superfamily of transcription factors (3).Massaro and co-workers (4,5) reported that all-trans retinoic acid increases the number of alveoli in rat lung. In the first study, postnatal rats that were treated with all-trans retinoic acid had increased numbers of alveoli and increased gas exchange surface area (4). A synthetic glucocorticoid, dexamethasone, decreases the number of alveoli in this animal model. All-trans retinoic acid overcame the inhibitory effects of dexamethasone on alveolarization in the postnatal rats (4). In the second study, elastase was insufflated into the lungs of adult rats to create a model of emphysema, i.e. the damaged lungs in the treated rats were characterized by fewer and larger alveoli and decreased gas exchange area (5). When the elastase-treated rats received an injection of all-trans retinoic acid, the emphysema-like effects of the elastase treatment were almost completely reversed, i...

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Section: Discussionmentioning

confidence: 99%

Alveolarization in Retinoic Acid Receptor-β–Deficient Mice

et al. 2005

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“…ER␤-deficient lungs have larger and fewer alveoli than normal lungs, indicating the importance of ER␤ in alveolarization (187). Expression of dominant negative RAR␣ in respiratory epithelial cells caused alveolar abnormalities consisting of increased airspace size and decreased alveolar surface area (268). Centrilobular emphysema, associated with decreased tropoelastin and increased MMP-9 production, was observed in Smad3 Ϫ/Ϫ mice (36).…”

Section: Alveolarization-postnatal Lung Morphogenesismentioning

confidence: 99%

Transcriptional Control of Lung Morphogenesis

Maeda

Davé²,

Whitsett³

2007

Physiological Reviews

432

387

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The vertebrate lung consists of multiple cell types that are derived primarily from endodermal and mesodermal compartments of the early embryo. The process of pulmonary organogenesis requires the generation of precise signaling centers that are linked to transcriptional programs that, in turn, regulate cell numbers, differentiation, and behavior, as branching morphogenesis and alveolarization proceed. This review summarizes knowledge regarding the expression and proposed roles of transcription factors influencing lung formation and function with particular focus on knowledge derived from the study of the mouse. A group of transcription factors active in the endodermally derived cells of the developing lung tubules, including thyroid transcription factor-1 (TTF-1), β-catenin, Forkhead orthologs (FOX), GATA, SOX, and ETS family members are required for normal lung morphogenesis and function. In contrast, a group of distinct proteins, including FOXF1, POD1, GLI, and HOX family members, play important roles in the developing lung mesenchyme, from which pulmonary vessels and bronchial smooth muscle develop. Lung formation is dependent on reciprocal signaling among cells of both endodermal and mesenchymal compartments that instruct transcriptional processes mediating lung formation and adaptation to breathing after birth.

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“…During microvascular maturation, the lung matures in a lung with a single-layer capillary bed [1] . Factors that play a role in the alveolarization process are Foxa2 [99] , GATA-6 [100] , plateletderived growth factor A (PDGF-A) [101] , TTF-1 [102] and RAR [103] . Factors important for the vascular maturation are VEGF [104,105] , MK [106] and Foxf1 [107] .…”

Section: Alveolar Period and Microvascular Maturationmentioning

confidence: 99%

The Molecular Basis for Abnormal Human Lung Development

2005

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Our understanding of lung development in the past two decades has moved from an anatomical to a histological basis and, most recently, to a molecular basis. Tissue interactions specify tracheal and lung primordia formation, program branching morphogenesis of the airway epithelium and regulate epithelial differentiation. In addition, lung development is influenced by mechanical and humoral factors. The regulatory molecules involved in morphogenetic signaling include growth and transcription factors and extracellular matrix molecules. These morphogenetic signals are responsible for lung patterning and differentiation. We will provide a brief overview of molecular signaling during early respiratory formation, airway branching, pulmonary vascularization and epithelial differentiation. We will then review aberrant morphogenetic signaling in human lung abnormalities, such as tracheoesophageal fistula, congenital diaphragmatic hernia, pulmonary hyperplasia, alveolar capillary dysplasia, congenital cystic adenomatoid malformation and bronchopulmonary dysplasia.

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Overexpression of Dominant Negative Retinoic Acid Receptor α Causes Alveolar Abnormality in Transgenic Neonatal Lungs

Cited by 39 publications

References 17 publications

Alveolarization in Retinoic Acid Receptor-β–Deficient Mice

Alveolarization in Retinoic Acid Receptor-β–Deficient Mice

Transcriptional Control of Lung Morphogenesis

The Molecular Basis for Abnormal Human Lung Development

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