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H. A. Marquez and F. Chen
the onset of embryonic lung formation, (Dersch and Zile 1993). A role for RA in the
branching morphogenesis of the avian lung has been shown recently by FernandesSilva and coworkers. The group treated embryonic lung explants with RA in vitro and
found that RA stimulates lung branching in a dose-dependent manner (FernandesSilva et al. 2017).
Development of the Field
Development of novel models/techniques for demonstrating the role of VA or RA in
lung development.
VA (retinol) enters cells by diffusion or via the transmembrane protein transporter,
STRA6 (stimulated by retinoic acid 6) (Kawaguchi et al. 2007; Noy 2016). Once in
the cytosol, it is oxidized into retinal in a reaction catalyzed by a retinol dehydrogenase (RDH or SDR) and then into RA in a reaction catalyzed by a retinal dehydrogenase (RALDH 1, 2, or 3; the corresponding genes are Aldh1a1-3) (Niederreither and
Dolle 2008). RA intracellular levels are sharply regulated by the action of enzymes
belonging to the cytochrome P450 26 subfamily (CYP26A1, B1, and C1) (MacLean
et al. 2001; Tahayato et al. 2003; White et al. 1996). To activate the signaling pathway, RA is transferred to the nucleus, where it binds specific retinoic acid nuclear
receptors (RARs). There are three subtypes (RARα, RARβ, and RARγ) that recognize specific DNA sequences called RARE (retinoic acid response element) in the
promoter region of RAR-specific target genes, including homeodomain genes (e.g.,
Hox genes), genes coding for RA signaling members (Rarβ, Cyp26a1), and genes
belonging to other signaling pathways such as FGF10, WNT, and TGFβ (Marquez
and Cardoso 2016) (Rochette-Egly, this volume).
Evidence points to the importance of RA for alveoli formation. During alveolarization, in the septating tissue close to type II alveolar epithelial cells of embryonic
rat lungs, there are lipid-rich mesenchymal cells (“lipofibroblasts”) containing high
levels of VA stores. These cells are important for alveolar formation (Burri 1974;
Dirami et al. 2004; Okabe et al. 1984) and are also found in humans, hamsters, and
mice (Kaplan et al. 1985). From late gestation to early postnatal life, rapid emptying
of the VA stores from these cells occurs, presumably due to an increased demand for
RA in lung maturation. (Geevarghese and Chytil 1994). These cells respond to RA in
an autocrine manner by upregulation of elastin, a major component of the extracellular matrix that is responsible for the elastic property of the lung (McGowan et al.
1997). In addition, these cells are believed to be the progenitors of myofibroblasts,
which are required for alveolar septation to proceed (Lindahl et al. 1997).
H. A. Marquez and F. Chen
the onset of embryonic lung formation, (Dersch and Zile 1993). A role for RA in the
branching morphogenesis of the avian lung has been shown recently by FernandesSilva and coworkers. The group treated embryonic lung explants with RA in vitro and
found that RA stimulates lung branching in a dose-dependent manner (FernandesSilva et al. 2017).
Development of the Field
Development of novel models/techniques for demonstrating the role of VA or RA in
lung development.
VA (retinol) enters cells by diffusion or via the transmembrane protein transporter,
STRA6 (stimulated by retinoic acid 6) (Kawaguchi et al. 2007; Noy 2016). Once in
the cytosol, it is oxidized into retinal in a reaction catalyzed by a retinol dehydrogenase (RDH or SDR) and then into RA in a reaction catalyzed by a retinal dehydrogenase (RALDH 1, 2, or 3; the corresponding genes are Aldh1a1-3) (Niederreither and
Dolle 2008). RA intracellular levels are sharply regulated by the action of enzymes
belonging to the cytochrome P450 26 subfamily (CYP26A1, B1, and C1) (MacLean
et al. 2001; Tahayato et al. 2003; White et al. 1996). To activate the signaling pathway, RA is transferred to the nucleus, where it binds specific retinoic acid nuclear
receptors (RARs). There are three subtypes (RARα, RARβ, and RARγ) that recognize specific DNA sequences called RARE (retinoic acid response element) in the
promoter region of RAR-specific target genes, including homeodomain genes (e.g.,
Hox genes), genes coding for RA signaling members (Rarβ, Cyp26a1), and genes
belonging to other signaling pathways such as FGF10, WNT, and TGFβ (Marquez
and Cardoso 2016) (Rochette-Egly, this volume).
Evidence points to the importance of RA for alveoli formation. During alveolarization, in the septating tissue close to type II alveolar epithelial cells of embryonic
rat lungs, there are lipid-rich mesenchymal cells (“lipofibroblasts”) containing high
levels of VA stores. These cells are important for alveolar formation (Burri 1974;
Dirami et al. 2004; Okabe et al. 1984) and are also found in humans, hamsters, and
mice (Kaplan et al. 1985). From late gestation to early postnatal life, rapid emptying
of the VA stores from these cells occurs, presumably due to an increased demand for
RA in lung maturation. (Geevarghese and Chytil 1994). These cells respond to RA in
an autocrine manner by upregulation of elastin, a major component of the extracellular matrix that is responsible for the elastic property of the lung (McGowan et al.
1997). In addition, these cells are believed to be the progenitors of myofibroblasts,
which are required for alveolar septation to proceed (Lindahl et al. 1997).