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E. Perl and J. S. Waxman
In contrast to mice, RARs appear to have distinct and non-redundant roles in other
vertebrates. For instance, in chick embryos, it has been shown that RARγ regulates
left-right patterning and looping during cardiac morphogenesis, while RARα2 is
required for the formation of the inflow tract (Romeih et al. 2003). Due to genome
duplication, zebrafish have 4 RARs (-αa, -αb, -γa, and -γb, yet lacking β genes) and
6 RXRs (-αa, -αb, -βa, -βb, -γa, and -γb) (Bertrand et al. 2007; Waxman and Yelon
2007). Although there is also significant redundancy between RARs in zebrafish
(Linville et al. 2009), we found that depletion of RARαb1 in zebrafish results in
cardiomegaly and increased CM specification (D’Aniello et al. 2013). Surprisingly,
these defects were caused by a gain in low levels of RA signaling that resulted from
inappropriate feedback.
Relevance
Downstream Effectors of RA Signaling During Heart
Development
Ultimately, the control of RA levels and the subsequent activation of RARs leads to
the regulation of many key transcription factors required during vertebrate cardiogenesis. Given the myriad specification and migration events that need to be integrated
for appropriate heart development, many of these transcription factors can be compartmentalized into their regulation of the earlier processes of cardiac progenitor
formation or in the regulation of later processes demarcated by the incorporation of
cells from the SHF.
Effectors of RA Signaling that Regulate Cardiac Progenitor Formation
With respect to early patterning, several members of the homeobox (Hox) transcription factor gene family are direct targets of RA (LaRosa and Gudas 1988; Marshall
et al. 1994; Dupé et al. 1997; Langston et al. 1997; Huang et al. 1998; Oosterveen et al.
2003). Hence, it is logical that Hox genes have been shown to be critical for proper
OFT development (Bertrand et al. 2011), which is consistent with the preponderance
of OFT defects observed when RA signaling components are perturbed.
During the early stages of cardiac development, lineage tracing experiments in
mice have revealed that SHF progenitors express Hoxa1, Hoxa3, and Hoxb1, which
are responsive to RA, and contribute to formation of the atria and inferior wall of
the OFT (Bertrand et al. 2011). Furthermore, the presence of enhancer-containing
RAREs in the Hoxb1 gene indicate that RA directly promotes Hoxb1 expression in
the SHF as well as in proepicardial progenitors (Nolte et al. 2013). Functionally,
Hoxb1 KO mice have VSDs and abnormal positioning of the great arteries. During
SHF addition, the OFTs of the Hoxb1 mutant mice are shorter than normal, due to
E. Perl and J. S. Waxman
In contrast to mice, RARs appear to have distinct and non-redundant roles in other
vertebrates. For instance, in chick embryos, it has been shown that RARγ regulates
left-right patterning and looping during cardiac morphogenesis, while RARα2 is
required for the formation of the inflow tract (Romeih et al. 2003). Due to genome
duplication, zebrafish have 4 RARs (-αa, -αb, -γa, and -γb, yet lacking β genes) and
6 RXRs (-αa, -αb, -βa, -βb, -γa, and -γb) (Bertrand et al. 2007; Waxman and Yelon
2007). Although there is also significant redundancy between RARs in zebrafish
(Linville et al. 2009), we found that depletion of RARαb1 in zebrafish results in
cardiomegaly and increased CM specification (D’Aniello et al. 2013). Surprisingly,
these defects were caused by a gain in low levels of RA signaling that resulted from
inappropriate feedback.
Relevance
Downstream Effectors of RA Signaling During Heart
Development
Ultimately, the control of RA levels and the subsequent activation of RARs leads to
the regulation of many key transcription factors required during vertebrate cardiogenesis. Given the myriad specification and migration events that need to be integrated
for appropriate heart development, many of these transcription factors can be compartmentalized into their regulation of the earlier processes of cardiac progenitor
formation or in the regulation of later processes demarcated by the incorporation of
cells from the SHF.
Effectors of RA Signaling that Regulate Cardiac Progenitor Formation
With respect to early patterning, several members of the homeobox (Hox) transcription factor gene family are direct targets of RA (LaRosa and Gudas 1988; Marshall
et al. 1994; Dupé et al. 1997; Langston et al. 1997; Huang et al. 1998; Oosterveen et al.
2003). Hence, it is logical that Hox genes have been shown to be critical for proper
OFT development (Bertrand et al. 2011), which is consistent with the preponderance
of OFT defects observed when RA signaling components are perturbed.
During the early stages of cardiac development, lineage tracing experiments in
mice have revealed that SHF progenitors express Hoxa1, Hoxa3, and Hoxb1, which
are responsive to RA, and contribute to formation of the atria and inferior wall of
the OFT (Bertrand et al. 2011). Furthermore, the presence of enhancer-containing
RAREs in the Hoxb1 gene indicate that RA directly promotes Hoxb1 expression in
the SHF as well as in proepicardial progenitors (Nolte et al. 2013). Functionally,
Hoxb1 KO mice have VSDs and abnormal positioning of the great arteries. During
SHF addition, the OFTs of the Hoxb1 mutant mice are shorter than normal, due to