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E. Perl and J. S. Waxman
is necessary for the proper invasion of the ventricular myocardium and limits these
cells from contributing to the coronary vasculature (Pérez-Pomares et al. 2002). Wt1
regulates an epithelial-to-mesenchymal transition (EMT) of the invading epicardial
cells and promotes ALDH1A2 expression in these cells (von Gise et al. 2011; Guadix
et al. 2011). However, wt1 expression is also responsive to RA within epicardial cells,
suggesting a feedback mechanism between these signals within this tissue.
Along with wt1, RA signaling promotes expression of the transcription factor
Tcf21, which limits epicardial progenitors from differentiating into smooth muscle
(Braitsch et al. 2012). Notably, loss of tcf21 in mice leads to neonatal lethality with
epicardial blistering, increased smooth muscle differentiation on the heart’s surface,
and a paucity of interstitial fibroblasts. However, both the endothelial differentiation
of coronary vessels and the epicardial EMT are relatively unaffected (Braitsch et al.
2012).
In terms of its role in myocardial expansion, the epicardium generates a feed
forward loop driven by the release of RA, which induces hepatic erythropoietin to
activate Igf2 (Stuckmann et al. 2003; Brade et al. 2011). CM proliferation through
various growth pathways, including Pi3K/ERK, Fgf and Wnt signaling, are thus
directly under the control of RA signaling (Kang and Sucov 2005; Lavine et al. 2005;
Merki et al. 2005; Lin et al. 2010). Interestingly, increased ALDH1A2 expression
throughout the epicardium is one of the first responses in injured adult zebrafish
hearts (Lepilina et al. 2006; Kikuchi et al. 2011; Itou et al. 2012). RA signaling
in the epicardium and endocardium is required for proper regeneration of the adult
zebrafish heart after injury. The interplay of these pathways as downstream effectors
of RA suggests that an improved understanding of RA signaling has the potential to
yield therapeutic applications within the domain of regenerative medicine.
The Future
While significant progress has been made in understanding the requirements of proper
RA signaling during vertebrate heart development since the initial insights provided
by Wilson and Warkany, there is still a considerable way to go before we have
a complete understanding of the precise transcriptional and cellular mechanisms
by which proper RA signaling directs all its various roles in heart development.
We have only discussed the interactions between RARs and a small sampling of
transcription factors here. However, it is likely that RA signaling controls highly
complex gene regulatory networks, which until now have largely been inaccessible
in these developmental contexts.
Recent advances in sequencing techniques have led to an explosion in our ability to
understand transcriptional and epigenetic mechanisms and how they impact the identity of individual cells in development and disease. Until recently, the major insights
regarding the transcriptional mechanisms by which RA signaling works have largely
been gained from studies of cultured cells and techniques that require large numbers
of cells, such as Chromatin Immunoprecipitation and high throughput sequencing
E. Perl and J. S. Waxman
is necessary for the proper invasion of the ventricular myocardium and limits these
cells from contributing to the coronary vasculature (Pérez-Pomares et al. 2002). Wt1
regulates an epithelial-to-mesenchymal transition (EMT) of the invading epicardial
cells and promotes ALDH1A2 expression in these cells (von Gise et al. 2011; Guadix
et al. 2011). However, wt1 expression is also responsive to RA within epicardial cells,
suggesting a feedback mechanism between these signals within this tissue.
Along with wt1, RA signaling promotes expression of the transcription factor
Tcf21, which limits epicardial progenitors from differentiating into smooth muscle
(Braitsch et al. 2012). Notably, loss of tcf21 in mice leads to neonatal lethality with
epicardial blistering, increased smooth muscle differentiation on the heart’s surface,
and a paucity of interstitial fibroblasts. However, both the endothelial differentiation
of coronary vessels and the epicardial EMT are relatively unaffected (Braitsch et al.
2012).
In terms of its role in myocardial expansion, the epicardium generates a feed
forward loop driven by the release of RA, which induces hepatic erythropoietin to
activate Igf2 (Stuckmann et al. 2003; Brade et al. 2011). CM proliferation through
various growth pathways, including Pi3K/ERK, Fgf and Wnt signaling, are thus
directly under the control of RA signaling (Kang and Sucov 2005; Lavine et al. 2005;
Merki et al. 2005; Lin et al. 2010). Interestingly, increased ALDH1A2 expression
throughout the epicardium is one of the first responses in injured adult zebrafish
hearts (Lepilina et al. 2006; Kikuchi et al. 2011; Itou et al. 2012). RA signaling
in the epicardium and endocardium is required for proper regeneration of the adult
zebrafish heart after injury. The interplay of these pathways as downstream effectors
of RA suggests that an improved understanding of RA signaling has the potential to
yield therapeutic applications within the domain of regenerative medicine.
The Future
While significant progress has been made in understanding the requirements of proper
RA signaling during vertebrate heart development since the initial insights provided
by Wilson and Warkany, there is still a considerable way to go before we have
a complete understanding of the precise transcriptional and cellular mechanisms
by which proper RA signaling directs all its various roles in heart development.
We have only discussed the interactions between RARs and a small sampling of
transcription factors here. However, it is likely that RA signaling controls highly
complex gene regulatory networks, which until now have largely been inaccessible
in these developmental contexts.
Recent advances in sequencing techniques have led to an explosion in our ability to
understand transcriptional and epigenetic mechanisms and how they impact the identity of individual cells in development and disease. Until recently, the major insights
regarding the transcriptional mechanisms by which RA signaling works have largely
been gained from studies of cultured cells and techniques that require large numbers
of cells, such as Chromatin Immunoprecipitation and high throughput sequencing