5 Retinoic Acid Signaling and Heart Development
125
Stainier and Fishman found that increasing concentrations of RA exposure caused
the sequential deletion of cardiac chambers beginning at the bulbus arteriosus and
progressing to the ventricle, atrium, and sinus venosus (Stainier and Fishman 1992).
While these results led the authors to conclude that RA affects cardiac development
along the A-P axis, several of their other findings suggested an alternative hypothesis:
first, they noted that with a progressive increase in RA exposure, parts of chambers
were deleted before entire chambers; and second, they observed that sensitivity to
RA appeared to be independent of chamber boundaries (Stainier and Fishman 1992).
Indeed, several of our own studies have since demonstrated that CM specification
can be completely eliminated with high levels of RA, while lower levels can actually differentially promote chamber-specific specification in a non-intuitive manner
(Waxman and Yelon 2009; D’Aniello et al. 2013).
RA Signaling Effects on Mouse Heart Development
Although genetic knock out (KO) studies of the RA receptors in mice had produced
congenital heart defects that resembled aspects of VAD embryos (Mendelsohn et al.
1994; Sucov et al. 1994; Ghyselinck et al. 1998), it was the targeted disruption of the
major embryonic RA-producing enzyme, Aldehyde dehydrogenase 1, family member A2 (ALDH1A2—formerly called RALDH2) that demonstrated the significant
requirement of RA signaling in mammalian heart development (Niederreither et al.
1999). Niederreither et al. found that Aldh1a2
–/ – embryos died at midgestation due
to multiple pleotropic defects, including a severely dysmorphic heart consisting of a
single, medial, dilated cavity. The lack of activity from RA-responsive transgenes,
the altered expression of an RA-responsive gene, and the near complete rescue of
the mutant phenotype by maternal RA supplementation established that RA was
specifically and absolutely required for embryo heart development.
The First Hypothesis for the Effects of RA: Atrial-Ventricular Patterning
Proper RA signaling is required for multiple aspects of vertebrate heart development,
including early patterning of the heart field, proper OFT development, epicardial
cell determination, and cardiac regeneration. However, the most debated role has
been with respect to its function in early cardiac progenitor patterning. The primary
hypotheses postulating a mechanism for RA-dependent cardiac pathologies developed from the understanding that RA signaling is both necessary and sufficient for
proper patterning of the A-P axis early in vertebrate embryogenesis (Durston et al.
1989; Sive et al. 1990).
At least in chicken embryos, subsequent fate maps initially supported the idea
that ventricular and atrial CM progenitors appear to be positioned in a relatively
A-P orientation within the ALPM (Hochgreb et al. 2003). Hence, the first hypothesis
about the role of RA signaling on heart development posited that RA supported atrial
cell identity at the expense of ventricular identity (Fig. 5.2).
125
Stainier and Fishman found that increasing concentrations of RA exposure caused
the sequential deletion of cardiac chambers beginning at the bulbus arteriosus and
progressing to the ventricle, atrium, and sinus venosus (Stainier and Fishman 1992).
While these results led the authors to conclude that RA affects cardiac development
along the A-P axis, several of their other findings suggested an alternative hypothesis:
first, they noted that with a progressive increase in RA exposure, parts of chambers
were deleted before entire chambers; and second, they observed that sensitivity to
RA appeared to be independent of chamber boundaries (Stainier and Fishman 1992).
Indeed, several of our own studies have since demonstrated that CM specification
can be completely eliminated with high levels of RA, while lower levels can actually differentially promote chamber-specific specification in a non-intuitive manner
(Waxman and Yelon 2009; D’Aniello et al. 2013).
RA Signaling Effects on Mouse Heart Development
Although genetic knock out (KO) studies of the RA receptors in mice had produced
congenital heart defects that resembled aspects of VAD embryos (Mendelsohn et al.
1994; Sucov et al. 1994; Ghyselinck et al. 1998), it was the targeted disruption of the
major embryonic RA-producing enzyme, Aldehyde dehydrogenase 1, family member A2 (ALDH1A2—formerly called RALDH2) that demonstrated the significant
requirement of RA signaling in mammalian heart development (Niederreither et al.
1999). Niederreither et al. found that Aldh1a2
–/ – embryos died at midgestation due
to multiple pleotropic defects, including a severely dysmorphic heart consisting of a
single, medial, dilated cavity. The lack of activity from RA-responsive transgenes,
the altered expression of an RA-responsive gene, and the near complete rescue of
the mutant phenotype by maternal RA supplementation established that RA was
specifically and absolutely required for embryo heart development.
The First Hypothesis for the Effects of RA: Atrial-Ventricular Patterning
Proper RA signaling is required for multiple aspects of vertebrate heart development,
including early patterning of the heart field, proper OFT development, epicardial
cell determination, and cardiac regeneration. However, the most debated role has
been with respect to its function in early cardiac progenitor patterning. The primary
hypotheses postulating a mechanism for RA-dependent cardiac pathologies developed from the understanding that RA signaling is both necessary and sufficient for
proper patterning of the A-P axis early in vertebrate embryogenesis (Durston et al.
1989; Sive et al. 1990).
At least in chicken embryos, subsequent fate maps initially supported the idea
that ventricular and atrial CM progenitors appear to be positioned in a relatively
A-P orientation within the ALPM (Hochgreb et al. 2003). Hence, the first hypothesis
about the role of RA signaling on heart development posited that RA supported atrial
cell identity at the expense of ventricular identity (Fig. 5.2).