5 Retinoic Acid Signaling and Heart Development
131
direct targets, given the realization that RA’s many effects are mediated by its direct
transcriptional output.
Congenital Heart Defects Due to the Disruption of RA Precursor Storage
and Transport
Establishing proper RA signaling at many different stages, in addition to patterning of the embryonic axis, is crucial for normal vertebrate heart development. The
requirement for proper RA signaling levels is emphasized by the fact that perturbation of nearly every step in the synthesis of RA or of it’s signaling mediators can
result in congenital heart anomalies or can induce a high sensitivity to VAD.
In humans, Matthew Wood Syndrome is associated with mutations in the transmembrane retinol transporter, Stimulated by retinoic acid 6 (STRA6), at the level
of retinol entry into the cell. Matthew Wood Syndrome is characterized by dextrocardia, OFT and septal defects (Fig. 5.5 and Table 5.1) (Pasutto et al. 2007; Golzio
et al. 2007; Cubuk et al. 2016; Noy 2016). Although stra6 KO mice have only ocular
defects and a diminished diurnal insulin response (Ruiz et al. 2012; Berry et al. 2013;
Amengual et al. 2014; Gliniak et al. 2017), stra6-depleted zebrafish embryos depict
heart defects (Isken et al. 2008).
Surprisingly, mouse KOs of the extracellular retinol transport protein, Retinol
binding protein 4 (Rbp4), which interacts with STRA6 to promote retinol entry into
the cell, and Lecithin retinol acyltransferase (Lrat), which converts retinol into retinyl
ester for storage, do not overtly affect embryonic development (Quadro et al. 1999;
Batten et al. 2004). However, rbp4 null mice do have transient trabeculation defects
and increased fibronectin deposition (Wendler et al. 2003).
In zebrafish, lratb depletion produces a similar overt phenotype to stra6 depletion,
which was interpreted as consistent with elevated embryonic RA (Isken et al. 2007).
However, the exact nature of the heart defects reported with loss of stra6 and lratb
needs to be examined in greater detail and confirmed with engineered zebrafish
mutants. Although loss of rbp4 and lrat alone in mice seems to be generally tolerated,
rbp4 and lrat;rbp4 double KOs are highly sensitized to VAD, which suggests that
both of these proteins may have more of a role in maintaining adequate levels of RA
during embryogenesis, rather than generating RA (Quadro et al. 2005; Kim et al.
2008).
In contrast to the aforementioned proteins, mice null for Dehydrogenase/reductase
3 (dhrs3), the reductase responsible for converting retinal into retinol, exhibit a
spectrum of congenital heart defects. dhrs3 is induced by RA signaling and produces
increases in RA signaling in both mice and zebrafish, consistent with its role in
limiting RA production (Feng et al. 2010; Billings et al. 2013; Adams et al. 2014;
Wang et al. 2018). dhrs3 KO mice have OFT and septal defects (Table 5.1) (Billings
et al. 2013), as well as aberrant invasion and migration of the epicardial cells into
the myocardium that results in thinning of the myocardium and aberrant coronary
vessel formation (Wang et al. 2018).
131
direct targets, given the realization that RA’s many effects are mediated by its direct
transcriptional output.
Congenital Heart Defects Due to the Disruption of RA Precursor Storage
and Transport
Establishing proper RA signaling at many different stages, in addition to patterning of the embryonic axis, is crucial for normal vertebrate heart development. The
requirement for proper RA signaling levels is emphasized by the fact that perturbation of nearly every step in the synthesis of RA or of it’s signaling mediators can
result in congenital heart anomalies or can induce a high sensitivity to VAD.
In humans, Matthew Wood Syndrome is associated with mutations in the transmembrane retinol transporter, Stimulated by retinoic acid 6 (STRA6), at the level
of retinol entry into the cell. Matthew Wood Syndrome is characterized by dextrocardia, OFT and septal defects (Fig. 5.5 and Table 5.1) (Pasutto et al. 2007; Golzio
et al. 2007; Cubuk et al. 2016; Noy 2016). Although stra6 KO mice have only ocular
defects and a diminished diurnal insulin response (Ruiz et al. 2012; Berry et al. 2013;
Amengual et al. 2014; Gliniak et al. 2017), stra6-depleted zebrafish embryos depict
heart defects (Isken et al. 2008).
Surprisingly, mouse KOs of the extracellular retinol transport protein, Retinol
binding protein 4 (Rbp4), which interacts with STRA6 to promote retinol entry into
the cell, and Lecithin retinol acyltransferase (Lrat), which converts retinol into retinyl
ester for storage, do not overtly affect embryonic development (Quadro et al. 1999;
Batten et al. 2004). However, rbp4 null mice do have transient trabeculation defects
and increased fibronectin deposition (Wendler et al. 2003).
In zebrafish, lratb depletion produces a similar overt phenotype to stra6 depletion,
which was interpreted as consistent with elevated embryonic RA (Isken et al. 2007).
However, the exact nature of the heart defects reported with loss of stra6 and lratb
needs to be examined in greater detail and confirmed with engineered zebrafish
mutants. Although loss of rbp4 and lrat alone in mice seems to be generally tolerated,
rbp4 and lrat;rbp4 double KOs are highly sensitized to VAD, which suggests that
both of these proteins may have more of a role in maintaining adequate levels of RA
during embryogenesis, rather than generating RA (Quadro et al. 2005; Kim et al.
2008).
In contrast to the aforementioned proteins, mice null for Dehydrogenase/reductase
3 (dhrs3), the reductase responsible for converting retinal into retinol, exhibit a
spectrum of congenital heart defects. dhrs3 is induced by RA signaling and produces
increases in RA signaling in both mice and zebrafish, consistent with its role in
limiting RA production (Feng et al. 2010; Billings et al. 2013; Adams et al. 2014;
Wang et al. 2018). dhrs3 KO mice have OFT and septal defects (Table 5.1) (Billings
et al. 2013), as well as aberrant invasion and migration of the epicardial cells into
the myocardium that results in thinning of the myocardium and aberrant coronary
vessel formation (Wang et al. 2018).