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E. Perl and J. S. Waxman
Development of the Field
Insights into RA-Mediated Decisions
Stages of Heart Development in Different Vertebrates
The early stages of heart development are similar in all vertebrates (Fig. 5.1). Cardiac progenitors are specified in bilateral positions that will give rise to the anterior lateral plate mesoderm (ALPM). The progenitor cells then move toward the
midline, fuse and form the rudimentary heart tube. The differentiation of cardiac
progenitors is a continuous process, although functionally and genetically they can
be divided into two waves (Buckingham 2016): The earlier differentiating wave of
cardiac progenitors, which is termed the first heart field (FHF), forms this initial
heart tube. Subsequently, cardiac progenitors that are adjacent to the FHF progenitors in the pharyngeal mesoderm add to both poles of the developing heart. These
later-differentiating progenitors are termed the second heart field (SHF). In zebrafish,
which have a two-chambered heart, the SHF gives rise to almost half the ventricle
and the bulbous arteriosus in the outflow tract, and a small portion of the atrium
(Fig. 5.1) (Bakkers 2011; Staudt and Stainier 2012; Liu and Stainier 2012). In birds
and mammals, which have a more complex four-chambered heart, the SHF adds to
the heart as it undergoes looping and septation (Buckingham 2016). Furthermore, in
these vertebrates, the SHF contributes predominantly to the atria, the right ventricle,
and the outflow tract, while the left ventricle is derived from the FHF (Fig. 5.1).
RA Signaling Effects on Vertebrate Heart Development
Results from numerous studies have led to a realization that vertebrate heart development is a dynamic process that requires an appropriate level of RA signaling to
facilitate cardiac patterning, particularly during early stages of development. In vertebrates, VA (retinol) is supplied through the mother’s circulation (in amniotes) or
the yolk (in anamniotes) (D’Aniello and Waxman 2015). Following its uptake in
the developing embryo, retinol is bound by cellular retinol-binding proteins and is
oxidized into retinal by microsomal short-chain dehydrogenases/reductases and subsequently into RA by retinaldehyde dehydrogenases (D’Aniello and Waxman 2015).
In addition to elucidating RA’s regulation at every step of this process, since Wilson
and Warkany’s seminal experiments at Cincinnati Children’s Hospital (Wilson and
Warkany 1949, 1950a, b; Wilson et al. 1953), studies involving virtually all major
animal models have demonstrated that both a deficiency of and an excess of RA
signaling causes similar congenital heart defects across vertebrates (Pan and Baker
2007; Niederreither and Dollé 2008; Duester 2008; Waxman et al. 2008; Liu and
Stainier 2012; Schilling et al. 2012; Rydeen and Waxman 2014, 2016; Liu et al.
2018; De Bono et al. 2018).
E. Perl and J. S. Waxman
Development of the Field
Insights into RA-Mediated Decisions
Stages of Heart Development in Different Vertebrates
The early stages of heart development are similar in all vertebrates (Fig. 5.1). Cardiac progenitors are specified in bilateral positions that will give rise to the anterior lateral plate mesoderm (ALPM). The progenitor cells then move toward the
midline, fuse and form the rudimentary heart tube. The differentiation of cardiac
progenitors is a continuous process, although functionally and genetically they can
be divided into two waves (Buckingham 2016): The earlier differentiating wave of
cardiac progenitors, which is termed the first heart field (FHF), forms this initial
heart tube. Subsequently, cardiac progenitors that are adjacent to the FHF progenitors in the pharyngeal mesoderm add to both poles of the developing heart. These
later-differentiating progenitors are termed the second heart field (SHF). In zebrafish,
which have a two-chambered heart, the SHF gives rise to almost half the ventricle
and the bulbous arteriosus in the outflow tract, and a small portion of the atrium
(Fig. 5.1) (Bakkers 2011; Staudt and Stainier 2012; Liu and Stainier 2012). In birds
and mammals, which have a more complex four-chambered heart, the SHF adds to
the heart as it undergoes looping and septation (Buckingham 2016). Furthermore, in
these vertebrates, the SHF contributes predominantly to the atria, the right ventricle,
and the outflow tract, while the left ventricle is derived from the FHF (Fig. 5.1).
RA Signaling Effects on Vertebrate Heart Development
Results from numerous studies have led to a realization that vertebrate heart development is a dynamic process that requires an appropriate level of RA signaling to
facilitate cardiac patterning, particularly during early stages of development. In vertebrates, VA (retinol) is supplied through the mother’s circulation (in amniotes) or
the yolk (in anamniotes) (D’Aniello and Waxman 2015). Following its uptake in
the developing embryo, retinol is bound by cellular retinol-binding proteins and is
oxidized into retinal by microsomal short-chain dehydrogenases/reductases and subsequently into RA by retinaldehyde dehydrogenases (D’Aniello and Waxman 2015).
In addition to elucidating RA’s regulation at every step of this process, since Wilson
and Warkany’s seminal experiments at Cincinnati Children’s Hospital (Wilson and
Warkany 1949, 1950a, b; Wilson et al. 1953), studies involving virtually all major
animal models have demonstrated that both a deficiency of and an excess of RA
signaling causes similar congenital heart defects across vertebrates (Pan and Baker
2007; Niederreither and Dollé 2008; Duester 2008; Waxman et al. 2008; Liu and
Stainier 2012; Schilling et al. 2012; Rydeen and Waxman 2014, 2016; Liu et al.
2018; De Bono et al. 2018).