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E. Perl and J. S. Waxman
oligo-mediated depletion of proteins, this requires confirmation with engineered
mutants.
As described above, in aldh1a2/nls mutant zebrafish and Aldh1a2 KO mice, there
is a posterior expansion of cardiac progenitors (Keegan et al. 2005; Sirbu et al.
2008; Waxman et al. 2008; Ryckebüsch et al. 2010). In the Aldh1a2 KO mice, it
has been proposed that the loss of RA specifically affects the SHF, which fails to
differentiate, and consequently specifically causes the OFT defects observed in these
mice. However, Aldh1a2 KO mice have improperly localized cardiac neural crest
within the OFT, which may contribute to the OFT defects (El Robrini et al. 2016).
Congenital Heart Defects Due to Disruption of RA Degradation
RA is a potent teratogen. Hence, as mentioned above, loss of the cytochrome p450
enzyme CYP26 proteins can profoundly impact vertebrate heart development. In
all vertebrate embryos examined, CYP26A1 is the most prevalent RA-degrading
enzyme present during early development. It is predominantly expressed at the anterior and posterior poles of the embryo (Abu-Abed et al. 2001; Kudoh et al. 2002;
Dobbs-McAuliffe et al. 2004; Emoto et al. 2005). In humans, loss of CYP26A1
expression is associated with DiGeorge syndrome (DGS) (Roberts et al. 2006; Pennimpede et al. 2010), which results in OFT and aortic arch defects. DGS is predominantly associated with heterozygous deletion of the 22q11.2 region on chromosome
22 and defects attributed to loss of the gene encoding the transcription factor T-box
1 (TBX1) (Yagi et al. 2003).
Interestingly, Tbx1 also regulates SHF addition to both cardiac poles from a
common progenitor population (Théveniau-Ruissy et al. 2008; Rana et al. 2014).
During the early stages of heart tube elongation, a subset of Tbx1 expressing cells
in the posterior SHF have recently been shown to downregulate the arterial pole
progenitor program in mice via the expression of Tbx5, which is mutated in HoltOram (hand-heart) syndrome and is essential for venous pole development (De Bono
et al. 2018). Interestingly, blocking RA signaling in this population also leads to
AVSDs (Atrioventricular Septal Defect), as Tbx5 activation requires RA.
Studies in multiple systems have suggested that Tbx1 and RA signaling also
mutually repress one another during pharyngeal arch artery development, in part
through Tbx1 promoting Cyp26a1 expression (Roberts et al. 2005, 2006; Guris et al.
2006; Ryckebüsch et al. 2010). The spectrum of congenital malformations in mice
and zebrafish cyp26a1 mutants is consistent with increased RA levels (Abu-Abed
et al. 2001; Sakai et al. 2001; Niederreither et al. 2002a; Emoto et al. 2005; Hernandez et al. 2007; Uehara et al. 2007). The early patterning defects observed in
cyp26-deficient zebrafish embryos are not as dramatic as what can be induced with
high concentrations of RA treatment. The phenotypes observed in cyp26-deficient
zebrafish embryos from endogenous increases in RA are more similar to modest
increases from RA treatment. With respect to the heart, cyp26a1 KO mice alone
overtly have looping defects (Table 5.1) (Abu-Abed et al. 2001). However, compound cyp26a1 and cyp26c1 mutations produce more severe cardiac looping defects,
E. Perl and J. S. Waxman
oligo-mediated depletion of proteins, this requires confirmation with engineered
mutants.
As described above, in aldh1a2/nls mutant zebrafish and Aldh1a2 KO mice, there
is a posterior expansion of cardiac progenitors (Keegan et al. 2005; Sirbu et al.
2008; Waxman et al. 2008; Ryckebüsch et al. 2010). In the Aldh1a2 KO mice, it
has been proposed that the loss of RA specifically affects the SHF, which fails to
differentiate, and consequently specifically causes the OFT defects observed in these
mice. However, Aldh1a2 KO mice have improperly localized cardiac neural crest
within the OFT, which may contribute to the OFT defects (El Robrini et al. 2016).
Congenital Heart Defects Due to Disruption of RA Degradation
RA is a potent teratogen. Hence, as mentioned above, loss of the cytochrome p450
enzyme CYP26 proteins can profoundly impact vertebrate heart development. In
all vertebrate embryos examined, CYP26A1 is the most prevalent RA-degrading
enzyme present during early development. It is predominantly expressed at the anterior and posterior poles of the embryo (Abu-Abed et al. 2001; Kudoh et al. 2002;
Dobbs-McAuliffe et al. 2004; Emoto et al. 2005). In humans, loss of CYP26A1
expression is associated with DiGeorge syndrome (DGS) (Roberts et al. 2006; Pennimpede et al. 2010), which results in OFT and aortic arch defects. DGS is predominantly associated with heterozygous deletion of the 22q11.2 region on chromosome
22 and defects attributed to loss of the gene encoding the transcription factor T-box
1 (TBX1) (Yagi et al. 2003).
Interestingly, Tbx1 also regulates SHF addition to both cardiac poles from a
common progenitor population (Théveniau-Ruissy et al. 2008; Rana et al. 2014).
During the early stages of heart tube elongation, a subset of Tbx1 expressing cells
in the posterior SHF have recently been shown to downregulate the arterial pole
progenitor program in mice via the expression of Tbx5, which is mutated in HoltOram (hand-heart) syndrome and is essential for venous pole development (De Bono
et al. 2018). Interestingly, blocking RA signaling in this population also leads to
AVSDs (Atrioventricular Septal Defect), as Tbx5 activation requires RA.
Studies in multiple systems have suggested that Tbx1 and RA signaling also
mutually repress one another during pharyngeal arch artery development, in part
through Tbx1 promoting Cyp26a1 expression (Roberts et al. 2005, 2006; Guris et al.
2006; Ryckebüsch et al. 2010). The spectrum of congenital malformations in mice
and zebrafish cyp26a1 mutants is consistent with increased RA levels (Abu-Abed
et al. 2001; Sakai et al. 2001; Niederreither et al. 2002a; Emoto et al. 2005; Hernandez et al. 2007; Uehara et al. 2007). The early patterning defects observed in
cyp26-deficient zebrafish embryos are not as dramatic as what can be induced with
high concentrations of RA treatment. The phenotypes observed in cyp26-deficient
zebrafish embryos from endogenous increases in RA are more similar to modest
increases from RA treatment. With respect to the heart, cyp26a1 KO mice alone
overtly have looping defects (Table 5.1) (Abu-Abed et al. 2001). However, compound cyp26a1 and cyp26c1 mutations produce more severe cardiac looping defects,