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H. A. Marquez and F. Chen
fewer and large alveoli, and diminished alveolar surface area, all characteristics of
an alveolarization defect. This demonstrated that RA signaling through its receptors
is important for alveoli formation during the latest stage of lung development (Yang
et al. 2003).
Targeting All RA Signaling
It has been difficult to generate compound mutants that completely inhibit RA signaling. Indeed, as in the dietary VAD models, Rar
−/− , Aldh1a2
−/− , and Rdh10
−/−
mutants have not induced complete RA deficiency (RAD) due to the presence of other
RARs or RA biosynthesis enzymes. However, the fact that lung agenesis occurs in
most mammalian models of VAD/RAD indicates that VA and RA are essential for
primary lung bud formation and lung progenitor cell survival (Mollard et al. 2000;
Niederreither et al. 1999; Sandell et al. 2007; Wilson et al. 1953).
Other Vertebrate Models
The avian lung has recently emerged as an alternative model for studying branching
morphogenesis. Despite the structural differences between adult mammalian and
avian lungs, there are molecular and morphologic similarities during early development of the respiratory systems of birds and mammals. The chick model offers
advantages over the mammalian model because of its availability, low cost, ease of
culture and surgical manipulations due to external development outside of the mother.
The culture of the chick embryos also allows for modulation of complex signaling
pathways using pharmacologic agents or genetic manipulations (Moura 2019).
The frog Xenopus, has also become an unexpected model for studies of early
respiratory development (Rankin et al. 2016; Shifley et al. 2012; Wang et al. 2011;
Yin et al. 2010). Before metamorphosis, the morphologic and molecular events during
Xenopus’ early foregut and lung development are very similar to the early embryonic
phase of mouse foregut and lung development (E8.5–E10.5) (Rankin et al. 2015). The
abundant and externally-developing Xenopus embryos make them ideal for the study
of complex signaling pathways. It is easy to perform gain-of-function and loss-offunction experiments in these embryos by culturing them with various agonists and
antagonists, or by injecting them with nucleotides or antisense oligomer to modulate
expression of specific genes. A recent report reveals that lung specification, and
therefore lung morphogenesis, fails to occur in Xenopus embryos if they are cultured
in BMS493 or DEAB (Wang et al. 2011), or if they are injected with antisense
oligomers to knock down RA synthesis (Rankin et al. 2016).
H. A. Marquez and F. Chen
fewer and large alveoli, and diminished alveolar surface area, all characteristics of
an alveolarization defect. This demonstrated that RA signaling through its receptors
is important for alveoli formation during the latest stage of lung development (Yang
et al. 2003).
Targeting All RA Signaling
It has been difficult to generate compound mutants that completely inhibit RA signaling. Indeed, as in the dietary VAD models, Rar
−/− , Aldh1a2
−/− , and Rdh10
−/−
mutants have not induced complete RA deficiency (RAD) due to the presence of other
RARs or RA biosynthesis enzymes. However, the fact that lung agenesis occurs in
most mammalian models of VAD/RAD indicates that VA and RA are essential for
primary lung bud formation and lung progenitor cell survival (Mollard et al. 2000;
Niederreither et al. 1999; Sandell et al. 2007; Wilson et al. 1953).
Other Vertebrate Models
The avian lung has recently emerged as an alternative model for studying branching
morphogenesis. Despite the structural differences between adult mammalian and
avian lungs, there are molecular and morphologic similarities during early development of the respiratory systems of birds and mammals. The chick model offers
advantages over the mammalian model because of its availability, low cost, ease of
culture and surgical manipulations due to external development outside of the mother.
The culture of the chick embryos also allows for modulation of complex signaling
pathways using pharmacologic agents or genetic manipulations (Moura 2019).
The frog Xenopus, has also become an unexpected model for studies of early
respiratory development (Rankin et al. 2016; Shifley et al. 2012; Wang et al. 2011;
Yin et al. 2010). Before metamorphosis, the morphologic and molecular events during
Xenopus’ early foregut and lung development are very similar to the early embryonic
phase of mouse foregut and lung development (E8.5–E10.5) (Rankin et al. 2015). The
abundant and externally-developing Xenopus embryos make them ideal for the study
of complex signaling pathways. It is easy to perform gain-of-function and loss-offunction experiments in these embryos by culturing them with various agonists and
antagonists, or by injecting them with nucleotides or antisense oligomer to modulate
expression of specific genes. A recent report reveals that lung specification, and
therefore lung morphogenesis, fails to occur in Xenopus embryos if they are cultured
in BMS493 or DEAB (Wang et al. 2011), or if they are injected with antisense
oligomers to knock down RA synthesis (Rankin et al. 2016).