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Relationship: 2561
Title
Decreased, atRA concentration leads to Disruption, Progenitor cells of second heart field
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Inhibition of RALDH2 causes reduced all-trans retinoic acid levels, leading to transposition of the great arteries | adjacent | High | Low | Gina Mennen (send email) | Open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Unspecific |
Life Stage Applicability
Term | Evidence |
---|---|
Fetal |
Key Event Relationship Description
The biological plausibility between the ATRA gradient stimulating the patterning of the SHF is high, because vertebrate embryo-fetal cardiovascular development involves multiple steps and great knowledge is available including the importance of all-trans retinoic acid (ATRA) which has been reviewed in multiple papers (Brade et al., 2018; Duong & Waxman, 2021; Nakajima, 2019; Perl & Waxman, 2019; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). As different processes in embryodevelopment benefit from varying levels of ATRA, an ATRA gradient exists which is generated by multiple enzymes that synthesize and degrade ATRA to maintain the preferred balance (Kedishvili, 2013; Menegola et al., 2021; Tonk & Pennings, 2015). In case cells sense high ATRA levels, proteins involved in ATRA degradation or storage are stimulated (STRA6, DHRS3, CRBP1, CRABP2, LRAT, CYP26A1) and proteins involved in ATRA generation are decreased in expression (RBP4, RDH10, ALDH1A2). In case cells sense low ATRA levels, proteins involved in ATRA generation are stimulated (RBP4, RDH10, ALDH1A2) and proteins involved in ATRA degradation or storage are decreased in expression (STRA6, DHRS3, CRBP1, CRABP2, LRAT, CYP26A1) (Duong & Waxman, 2021).
This ATRA gradient during cardiovascular development induces correct patterning of progenitor cells and later correct looping of the heart tube to form a four-chambered heart including formation of the great vessels. In case this gradient is disturbed, cardiovascular developmental defects can occur (Nakajima, 2019; Perl & Waxman, 2019; Sirbu et al., 2020; Stefanovic & Zaffran, 2017).
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
The evidence for this KER has been studied in chick, zebrafish, and murine studies. The biological plausibility for ATRA involved in second heart field (SHF) patterning and signaling is strong. The human evidence on the other hand is not well known and although evolutionary there are many resemblances across species, there may be differences with human biology.
The second heart field is patterned along an anterior and posterior axis, which is important for consequent predispositioning to specific anatomical parts/occurrences in cardiovascular development. After the initial patterning stages, the size of the cardiac progenitor pool is controlled within the anterior lateral plate mesoderm, ATRA signaling then divides the anterior and posterior SHFs (Keegan et al., 2005; S. Wang & Moise, 2019). High ATRA signaling defines the posterior boundary of the murine second heart field (Ryckebusch et al., 2008a; Sirbu et al., 2008). This is exemplified by the ATRA producing enzyme RALDH, which is expressed in posterior SHF progenitors in mice (Stefanovic et al., 2020).
When comparing species, data from ATRA-deficient mice implied that ATRA signaling primarily affects SHF progenitor differentiation at the arterial and venous poles (Ryckebusch et al., 2008a; Sirbu et al., 2008), while data examining ATRA-deficient zebrafish suggested these embryos have enlarged hearts with an increase in FHF-derived cardiomyocytes (Duong & Waxman, 2021; Waxman et al., 2008).
ATRA signaling promotes expression of Tbx5 within the posterior SHF (de Bono et al., 2018; Duong & Waxman, 2021). Consequently, Tbx5 inhibits Tbx1 in the anterior SHF. Mef2c activation also needs ATRA signaling within the SHF progenitors (P. Li et al., 2010). ATRA signaling represses Fgf8 (Sorrell & Waxman, 2011). ATRA signaling activates Hox genes (Langston & Gudas, 1992; Marshall et al., 1996; Zhang et al., 2000). Hoxa3 expression in the SHF depends on ATRA signaling (Bertrand et al., 2011). Also, Hoxa1 (Ryckebusch et al., 2008a) and Hoxb1 are involved in SHF patterning (Bertrand et al., 2011; Dollé et al., 2010; Hochgreb et al., 2003; P. Li et al., 2010; Moss et al., 1998; Roux et al., 2015; Ryckebusch et al., 2008a; Sirbu et al., 2008; Stefanovic et al., 2020). All these genes are involved in AP patterning.
Empirical Evidence
The evidence for the relationship of ATRA gradient formation and SHF patterning is well established and nicely summarized by Nakajima (2019). The posterior part of the SHF is in need of a strong ATRA signaling that inhibits Tbx1 to define the posterior SHF boundary. Low-weak ATRA signaling stimulates the expression of Tbx1 in the anterior SHF. The anterior SHF consists of progenitors for the formation of the outflow tract (OFT). Additionally, the anterior SHF’s cranial segments consisting of pharyngeal arches 1-2 and are responsible for the formation of the right ventricle and proximal OFT. The anterior SHF’s caudal segments consisting of the pharyngeal arches 3-6 are responsible for distal OFT formation and the ascending aorta (AA). The aortic arch within pharyngeal arch 4 will eventually form the ascending aorta.
Evidence for this relationship mainly comes from knockout studies. Mutations of the Rdh and Raldh2 gene result in phenotypes characterized by prominent myocardial defects as severe ventricular myocardium hypoplasia resulting in embryonic lethality (Brade et al., 2011; el Robrini et al., 2016; Merki et al., 2005; Niederreither et al., 1997, 2001; Sorrell & Waxman, 2011; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). These Raldh2 mouse mutant embryos show a disruption of the posterior limit of the SHF starting at E7.5 (Duong & Waxman, 2021; Ryckebusch et al., 2008a; Sirbu et al., 2008).
Excess exposure in human to vitamin A or the analogues (e.g. ATRA), can cause defects including conotruncal and aortic arch artery malformations like great vessel transposition, right ventricle double outlet, and teratology of Fallot (Stefanovic & Zaffran, 2017). This is also observed when rodents were treated with ATRA including transposition of great arteries and patterning defects (Stefanovic & Zaffran, 2017). In vitro experiments confirmed the in vivo observations because cultured SHF progenitors failed to differentiate from the arterial pole of Aldh1a2KO mice (Ryckebusch et al., 2008b).
Uncertainties and Inconsistencies
ATRA levels can also be diminished through a feedback loop by for instance Cyp26. For creating an ATRA gradient, the Cyp26a1 negative feedback loop is critical as was confirmed when coupling in vivo zebrafish studies with mathematical modeling (A. Q. Cai et al., 2012; Duong & Waxman, 2021; Schilling et al., 2012; White et al., 2007).
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
Bertrand, N., Roux, M., Ryckebüsch, L., Niederreither, K., Dollé, P., Moon, A., Capecchi, M., & Zaffran, S. (2011). Hox genes define distinct progenitor sub-domains within the second heart field. Developmental Biology, 353(2), 266–274. https://doi.org/10.1016/J.YDBIO.2011.02.029
Brade, T., Kumar, S., Cunningham, T. J., Chatzi, C., Zhao, X., Cavallero, S., Li, P., Sucov, H. M., Ruiz-Lozano, P., & Duester, G. (2011). Retinoic acid stimulates myocardial expansion by induction of hepatic erythropoietin which activates epicardial Igf2. Development, 138(1), 139–148. https://doi.org/10.1242/dev.054239
Brade, T., Pane, L. S., Moretti, A., Chien, K. R., & Laugwitz, K.-L. (2018). Embryonic Heart Progenitors and Cardiogenesis. 1–18. https://doi.org/10.1101/cshperspect.a013847
Cai, A. Q., Radtke, K., Linville, A., Lander, A. D., Nie, Q., & Schilling, T. F. (2012). Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish. Development (Cambridge, England), 139(12), 2150–2155. https://doi.org/10.1242/DEV.077065
de Bono, C., Thellier, C., Bertrand, N., Sturny, R., Jullian, E., Cortes, C., Stefanovic, S., Zaffran, S., Théveniau-Ruissy, M., & Kelly, R. G. (2018). T-box genes and retinoic acid signaling regulate the segregation of arterial and venous pole progenitor cells in the murine second heart field. Human Molecular Genetics, 27(21), 3747–3760. https://doi.org/10.1093/HMG/DDY266
Dollé, P., Fraulob, V., Gallego-Llamas, J., Vermot, J., & Niederreither, K. (2010). Fate of retinoic acid-activated embryonic cell lineages. Developmental Dynamics : An Official Publication of the American Association of Anatomists, 239(12), 3260–3274. https://doi.org/10.1002/DVDY.22479
Duong, T. B., & Waxman, J. S. (2021). Patterning of vertebrate cardiac progenitor fields by retinoic acid signaling. Genesis (New York, N.Y. : 2000), e23458. https://doi.org/10.1002/dvg.23458
el Robrini, N., Etchevers, H. C., Ryckebüsch, L., Faure, E., Eudes, N., Niederreither, K., Zaffran, S., & Bertrand, N. (2016). Cardiac outflow morphogenesis depends on effects of retinoic acid signaling on multiple cell lineages. Developmental Dynamics, 245(3), 388–401. https://doi.org/10.1002/dvdy.24357
Hochgreb, T., Linhares, V. L., Menezes, D. C., Sampaio, A. C., Yan, C. Y. I., Cardoso, W. v., Rosenthal, N., & Xavier-Neto, J. (2003). A caudorostral wave of RALDH2 conveys anteroposterior information to the cardiac field. Development, 130(22), 5363–5374. https://doi.org/10.1242/DEV.00750
Kedishvili, N. Y. (2013). Enzymology of retinoic acid biosynthesis and degradation. Journal of Lipid Research, 54(7), 1744–1760. https://doi.org/10.1194/JLR.R037028
Keegan, B. R., Feldman, J. L., Begemann, G., Ingham, P. W., & Yelon, D. (2005). Retinoic acid signaling restricts the cardiac progenitor pool. Science (New York, N.Y.), 307(5707), 247–249. https://doi.org/10.1126/SCIENCE.1101573
Langston, A. W., & Gudas, L. J. (1992). Identification of a retinoic acid responsive enhancer 3’ of the murine homeobox gene Hox-1.6. Mechanisms of Development, 38(3), 217–227. https://doi.org/10.1016/0925-4773(92)90055-O
Li, P., Pashmforoush, M., & Sucov, H. M. (2010). Retinoic Acid Regulates Differentiation of the Secondary Heart Field and TGFβ-Mediated Outflow Tract Septation. Developmental Cell, 18(3), 480–485. https://doi.org/10.1016/J.DEVCEL.2009.12.019/ATTACHMENT/B413E05D-04E2-4F76-9417-72BF1FD02515/MMC1.PDF
Marshall, H., Morrison, A., Studer, M., Popperl, H., & Krumlauf’, R. (1996). Retinoids and Hox genes. The FASEB Journal, 10(9), 969–978. https://doi.org/10.1096/FASEBJ.10.9.8801179
Menegola, E., Veltman, C. H. J., Battistoni, M., di Renzo, F., Moretto, A., Metruccio, F., Beronius, A., Zilliacus, J., Kyriakopoulou, K., Spyropoulou, A., Machera, K., van der Ven, L. T. M., & Luijten, M. (2021). An adverse outcome pathway on the disruption of retinoic acid metabolism leading to developmental craniofacial defects. Toxicology, 458. https://doi.org/10.1016/J.TOX.2021.152843
Merki, E., Zamora, M., Raya, A., Kawakami, Y., Wang, J., Zhang, X., Burch, J., Kubalak, S. W., Kaliman, P., Belmonte, J. C. I., Chien, K. R., & Ruiz-Lozano, P. (2005). Epicardial retinoid X receptor alpha is required for myocardial growth and coronary artery formation. Proceedings of the National Academy of Sciences of the United States of America, 102(51), 18455–18460. https://doi.org/10.1073/PNAS.0504343102
Moss, J. B., Xavier-Neto, J., Shapiro, M. D., Nayeem, S. M., McCaffery, P., Dräger, U. C., & Rosenthal, N. (1998). Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart. Developmental Biology, 199(1), 55–71. https://doi.org/10.1006/dbio.1998.8911
Nakajima, Y. (2019). Retinoic acid signaling in heart development. Genesis, 57(7). https://doi.org/10.1002/dvg.23300
Niederreither, K., McCaffery, P., Dräger, U. C., Chambon, P., & Dollé, P. (1997). Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mechanisms of Development, 62(1), 67–78. https://doi.org/10.1016/S0925-4773(96)00653-3
Niederreither, K., Vermot, J., Messaddeq, N., Schuhbaur, B., Chambon, P., & Dollé, P. (2001). Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development (Cambridge, England), 128(7), 1019–1031. https://doi.org/10.1242/dev.128.7.1019
Perl, E., & Waxman, J. S. (2019). Reiterative Mechanisms of Retinoic Acid Signaling during Vertebrate Heart Development. Journal of Developmental Biology, 7(2). https://doi.org/10.3390/jdb7020011
Roux, M., Laforest, B., Capecchi, M., Bertrand, N., & Zaffran, S. (2015). Hoxb1 regulates proliferation and differentiation of second heart field progenitors in pharyngeal mesoderm and genetically interacts with Hoxa1 during cardiac outflow tract development. Developmental Biology, 406(2), 247–258. https://doi.org/10.1016/J.YDBIO.2015.08.015
Ryckebusch, L., Wang, Z., Bertrand, N., Lin, S. C., Chi, X., Schwartz, R., Zaffran, S., & Niederreither, K. (2008a). Retinoic acid deficiency alters second heart field formation. Proceedings of the National Academy of Sciences of the United States of America, 105(8), 2913–2918. https://doi.org/10.1073/PNAS.0712344105
Ryckebusch, L., Wang, Z., Bertrand, N., Lin, S. C., Chi, X., Schwartz, R., Zaffran, S., & Niederreither, K. (2008b). Retinoic acid deficiency alters second heart field formation. Proceedings of the National Academy of Sciences of the United States of America, 105(8), 2913–2918. https://doi.org/10.1073/PNAS.0712344105
Schilling, T. F., Nie, Q., & Lander, A. D. (2012). Dynamics and precision in retinoic acid morphogen gradients. Current Opinion in Genetics & Development, 22(6), 562–569. https://doi.org/10.1016/J.GDE.2012.11.012
Sirbu, I. O., Chiş, A. R., & Moise, A. R. (2020). Role of carotenoids and retinoids during heart development. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1865(11). https://doi.org/10.1016/j.bbalip.2020.158636
Sirbu, I. O., Zhao, X., & Duester, G. (2008). Retinoic acid controls heart anteroposterior patterning by down-regulating Isl1 through the Fgf8 pathway. Developmental Dynamics : An Official Publication of the American Association of Anatomists, 237(6), 1627–1635. https://doi.org/10.1002/DVDY.21570
Sorrell, M. R. J., & Waxman, J. S. (2011). Restraint of Fgf8 signaling by retinoic acid signaling is required for proper heart and forelimb formation. Developmental Biology, 358(1), 44–55. https://doi.org/10.1016/J.YDBIO.2011.07.022
Stefanovic, S., Laforest, B., Desvignes, J. P., Lescroart, F., Argiro, L., Maurel-Zaffran, C., Salgado, D., Plaindoux, E., de Bono, C., Pazur, K., Théveniau-Ruissy, M., Béroud, C., Puceat, M., Gavalas, A., Kelly, R. G., & Zaffran, S. (2020). Hox-dependent coordination of mouse cardiac progenitor cell patterning and differentiation. ELife, 9, 1–32. https://doi.org/10.7554/ELIFE.55124
Stefanovic, S., & Zaffran, S. (2017). Mechanisms of retinoic acid signaling during cardiogenesis. Mechanisms of Development, 143, 9–19. https://doi.org/10.1016/j.mod.2016.12.002
Tonk, E. C. M., & Pennings, J. L. A. (2015). An adverse outcome pathway framework for neural tube and axial defects mediated by modulation of retinoic acid homeostasis. Reproductive Toxicology, 55, 104–113. https://doi.org/10.1016/J.REPROTOX.2014.10.008
Wang, S., & Moise, A. R. (2019). Recent insights on the role and regulation of retinoic acid signaling during epicardial development. Genesis, 57(7). https://doi.org/10.1002/dvg.23303
Waxman, J. S., Keegan, B. R., Roberts, R. W., Poss, K. D., & Yelon, D. (2008). Hoxb5b acts downstream of retinoic acid signaling in the forelimb field to restrict heart field potential in zebrafish. Developmental Cell, 15(6), 923–934. https://doi.org/10.1016/J.DEVCEL.2008.09.009
White, R. J., Nie, Q., Lander, A. D., & Schilling, T. F. (2007). Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biology, 5(11), 2522–2533. https://doi.org/10.1371/JOURNAL.PBIO.0050304
Zhang, F., Nagy Kovács, E., & Featherstone, M. S. (2000). Murine hoxd4 expression in the CNS requires multiple elements including a retinoic acid response element. Mechanisms of Development, 96(1), 79–89. https://doi.org/10.1016/S0925-4773(00)00377-4