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Review
. 2021 Nov;59(11):e23458.
doi: 10.1002/dvg.23458. Epub 2021 Oct 19.

Patterning of vertebrate cardiac progenitor fields by retinoic acid signaling

Tiffany B Duong  1   2 , Joshua S Waxman  2   3
Affiliations
Review

Patterning of vertebrate cardiac progenitor fields by retinoic acid signaling

Tiffany B Duong et al. Genesis. 2021 Nov.

Abstract

The influence of retinoic acid (RA) signaling on vertebrate development has a well-studied history. Cumulatively, we now understand that RA signaling has a conserved requirement early in development restricting cardiac progenitors within the anterior lateral plate mesoderm of vertebrate embryos. Moreover, genetic and pharmacological manipulations of RA signaling in vertebrate models have shown that proper heart development is achieved through the deployment of positive and negative feedback mechanisms, which maintain appropriate RA levels. In this brief review, we present a chronological overview of key work that has led to a current model of the critical role for early RA signaling in limiting the generation of cardiac progenitors within vertebrate embryos. Furthermore, we integrate the previous work in mice and our recent findings using zebrafish, which together show that RA signaling has remarkably conserved influences on the later-differentiating progenitor populations at the arterial and venous poles. We discuss how recognizing the significant conservation of RA signaling on the differentiation of these progenitor populations offers new perspectives and may impact future work dedicated to examining vertebrate heart development.

Keywords: cardiac progenitors; first heart field; patterning; retinoic acid signaling; second heart field; vertebrate heart development.

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Conflict of interest statement

Conflicts of Interest: The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. Schematic of cardiac progenitor fields and the requirements of early RA signaling in mice and zebrafish.
(A) (Upper) In wild-type (WT) mice at E7.5, the later-differentiating progenitors of the SHF (green) are located more medial and dorsal relative to the earlier-differentiating progenitors of the FHF (purple) (view is ventral). By E9.5, the murine heart has started to loop, with the FHF contributing to the left ventricle and inflow tract. By E10.5, the SHF has given rise to the OFT, majority of the right ventricle, and the atria in the nascent 4-chambered heart, while the FHF contributes predominantly to the left ventricle. Pacemaker cells of the SAN (yellow) reside within the upper right atria. (Lower) By E7.5 in RA-deficient (-RA) mice, there is a posterior expansion of the SHF within the ALPM relative to the WT mice, based on marker expression. By E9.5, the hearts of -RA mice are grossly dysmorphic and fail to loop, with SHF-derived cells at both the arterial and venous poles failing to differentiate. -RA (Aldh1a2 KO) mice embryos do not survive past E10.5. Illustrations based on images from Ryckebusch et al., (2008); Sirbu et al., (2008). (B) (Upper) In WT zebrafish at 16 hpf (17 somite stage), the bilateral cardiac progenitor populations are located within the ALPM, with the SHF progenitors that will give rise to the arterial ventricle and OFT located more anterior and medial to the FHF progenitors. By 72 hpf, WT zebrafish hearts are comprised of the SHF-derived ventricular cells and the BA (light orange) at the arterial pole as well as the venous cells of the SAN that are likely derived from the posterior SHF, although this has not been extensively mapped in zebrafish. Approximately half of the single ventricle and most of the atrial CMs are derived from the FHF. (Lower) In -RA zebrafish hearts, there is an expansion of the FHF within the ALPM. By 72 hpf in -RA zebrafish embryos, the hearts are enlarged due to differentiation of the surplus FHF-derived CMs. There is a loss of SHF-derived BA and ventricular CMs in the OFT at the arterial pole as well as a failure of pacemaker cells of the SAN within the venous pole to differentiate. Illustrations based on images from Duong et al., (2021). E - embryonic day; hpf - hours post-fertilization; LtA - left atrium; LtV - left ventricle; RtA - right atrium; RtV - right ventricle; A - atrium; V - ventricle.
Figure 2.
Figure 2.. Overview of the canonical RA signaling pathway.
Retinol bound to RBP4 in the bloodstream binds to its receptor STRA6, which mediates the cellular uptake of retinol and its release from RBP4. Retinol then binds to CRBP1 and can then undergo two consecutive enzymatic steps that convert retinol to RA. The first reversible oxidation is catalyzed by RDH10. The produced retinal is then irreversibly oxidized to RA by ALDH1A2. RA then binds to CRABP2 and is transported into the cell nucleus where it binds to RARs/RXRs. RA can also be distributed to CYP26 enzymes for degradation. RA bound to RARs/RXRs promotes transcription of target genes through RAREs. Prior to RA production, DHRS3 can facilitate the conversion of retinal to retinol for storage. Retinol can be transported to LRAT for esterification for storage as retinyl esters.
Figure 3.
Figure 3.. Schematic of RA feedback.
(Top) If cells sense high RA levels, they produce feedback that results in a decrease in expression (red) of key RA proteins involved in retinol uptake and generation, coupled with increased expression (green) of RA-limiting proteins. (Bottom) If cells sense low RA levels, they produce feedback that results in an increase in the expression (green) of the RA proteins involved in retinol uptake and generation and a decrease in the expression (red) of RA-limiting proteins. These negative and positive feedback mechanisms are designed to prevent significant fluctuations and are involved in generating gradients during embryonic development.
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