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Relationship: 2561

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decreased, atRA concentration leads to Disruption, Progenitor cells of second heart field

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Do not cite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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mouse Mus musculus NCBI
chicken Gallus gallus NCBI
zebrafish Danio rerio NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Fetal

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

  

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

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