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Relationship: 2563


The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Reduced neural crest cell migration leads to Transposition of the great arteries

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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 Do not cite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

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Neural crest cells (NCCs) migrate into the pharyngeal arches 3, 4, and 6. The cardiac NCCs (cNCCs) differentiate into smooth muscle cells (SMCs) between E10.5-E13.5 in mice and between HH14-HH28 in chicken. The left fourth pharyngeal arch artery (PAA) in mammals persists and forms the segment of the aortic arch (AA) connecting the aortic sac and the descending aorta. The sixth PAA will form the pulmonary veins.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   More help

The biological plausibility of this relationship is high. Abnormal cNCCs in mouse mutants show regression of the left fourth PAA resulting in an interrupted aortic arch (IAA) also referred to as type b interruption. cNCCs contribute to outflow tract (OFT) septation, vascular remodeling, cardiac valve formation, and possibly also to myocardial development and the conduction system (Plein et al., 2015). When comparing PAA development between taxa there is a difference in aortic arch anatomy. Avian species have a right-sided aortic arch and mammals have a left-sided aortic arch (Gittenberger-de Groot et al., 2006). The relationship between cNCCs and transposition of the great arteries became for the first time very clear in the chick-ablation model by Kirby et al. that showed a spectrum of aortic arch malformations with the fourth and sixth segments as being most vulnerable (Hutson & Kirby, 2007; Kirby, 1993; Kirby et al., 1983; Kirby & Waldo, 1995). This model was more difficult to copy in mammals, yet mouse knock-out models of endothelin 1, semaphoring 3 and Vegf164 could be traced to disturbed NCC migration and differentiation (Gittenberger-de Groot et al., 2006). As the role of cNCCs in OFT septation and aortic arch remodeling is critical in birds and mammals, this is less well understood in vertebrates (Chin et al., 2012). Zebrafish have a different circulation system as compared to mammals and e.g. don’t have a separate systemic and pulmonary circulation or an OFT septum, but they do have cNCCs. The cNCCs in zebrafish arise from a broader region of the neural tube and contributes to all cardiac regions (Chin et al., 2012; Sato et al., 2006).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

Despite the seemingly clear role of cNCCs in great artery formation, also other progenitors contribute to AAA remodeling that are in cross-talk with the cNCCs, such as the pharyngeal mesoderm and endoderm (Franco & Campione, 2003; Gittenberger-de Groot et al., 2006). Furthermore, cNCC ablation also results in altered SHF proliferation and abnormal myocardial function as secondary effects (Farrell et al., 2001; Farrell & Kirby, 2001; Leatherbury et al., 1990; Waldo et al., 2005).

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help


List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Aoto, K., Sandell, L. L., Butler Tjaden, N. E., Yuen, K. C., Watt, K. E. N., Black, B. L., Durnin, M., & Trainor, P. A. (2015). Mef2c-F10N enhancer driven β-galactosidase (LacZ) and Cre recombinase mice facilitate analyses of gene function and lineage fate in neural crest cells. Developmental Biology, 402(1), 3–16.

Chin, A. J., Saint-Jeannet, J. P., & Lo, C. W. (2012). How insights from cardiovascular developmental biology have impacted the care of infants and children with congenital heart disease. Mechanisms of Development, 129(5–8), 75–97.

Choudhary, B., Ito, Y., Makita, T., Sasaki, T., Chai, Y., & Sucov, H. M. (2006). Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFbeta receptor (Tgfbr2) mutant mice. Developmental Biology, 289(2), 420–429.

Clouthier, D. E., Hosoda, K., Richardson, J. A., Williams, S. C., Yanagisawa, H., Kuwaki, T., Kumada, M., Hammer, R. E., & Yanagisawai, M. (1998). Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development, 125(5), 813–824.

Creazzo, T. L., Godt, R. E., Leatherbury, L., Conway, S. J., & Kirby, M. L. (1998). Role of cardiac neural crest cells in cardiovascular development. Annual Review of Physiology, 60, 267–286.

Farrell, M. J., Burch, J. L., Wallis, K., Rowley, L., Kumiski, D., Stadt, H., Godt, R. E., Creazzo, T. L., & Kirby, M. L. (2001). FGF-8 in the ventral pharynx alters development of myocardial calcium transients after neural crest ablation. Journal of Clinical Investigation, 107(12), 1509–1517.

Farrell, M. J., & Kirby, M. L. (2001). Cell biology of cardiac development. International Review of Cytology, 202, 99–158.

Franco, D., & Campione, M. (2003). The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases. Trends in Cardiovascular Medicine, 13(4), 157–163.

Gittenberger-de Groot, A. C., Azhar, M., & Molin, D. G. M. (2006). Transforming growth factor beta-SMAD2 signaling and aortic arch development. Trends in Cardiovascular Medicine, 16(1), 1–6.

Gu, C., Rodriguez, E. R., Reimert, D. v., Shu, T., Fritzsch, B., Richards, L. J., Kolodkin, A. L., & Ginty, D. D. (2003). Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Developmental Cell, 5(1), 45–57.

High, F. A., Zhang, M., Proweller, A., Tu, L. L., Parmacek, M. S., Pear, W. S., & Epstein, J. A. (2007). An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. The Journal of Clinical Investigation, 117(2), 353–363.

Hutson, M. R., & Kirby, M. L. (2007). Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations. Seminars in Cell and Developmental Biology, 18(1), 101–110.

Jain, R., Engleka, K. A., Rentschler, S. L., Manderfield, L. J., Li, L., Yuan, L., & Epstein, J. A. (2011). Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves. Journal of Clinical Investigation, 121(1), 422–430.

Jain, R., Rentschler, S., & Epstein, J. A. (2010). Notch and cardiac outflow tract development. Annals of the New York Academy of Sciences, 1188, 184–190.

Jiang, X., Rowitch, D. H., Soriano, P., McMahon, A. P., & Sucov, H. M. (2000). Fate of the mammalian cardiac neural crest. Development, 127(8), 1607–1616.

Kameda, Y. (2009). Hoxa3 and signaling molecules involved in aortic arch patterning and remodeling. Cell and Tissue Research, 336(2), 165–178.

Kirby, M. L. (1993). Cellular and molecular contributions of the cardiac neural crest to cardiovascular development. Trends in Cardiovascular Medicine, 3(1), 18–23.

Kirby, M. L., Gale, T. F., & Stewart, D. E. (1983). Neural crest cells contribute to normal aorticopulmonary septation. Science, 220(4601), 1059–1061.

Kirby, M. L., & Waldo, K. L. (1995). Neural crest and cardiovascular patterning. Circulation Research, 77(2), 211–215.

Kubalak, S. W., Hutson, D. R., Scott, K. K., & Shannon, R. A. (2002). Elevated transforming growth factor β2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor α knockout embryos. Development, 129(3), 733–746.

Kurihara, Y., Kurihara, H., Oda, H., Maemura, K., Nagai, R., Ishikawa, T., & Yazaki, Y. (1995). Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1. Journal of Clinical Investigation, 96(1), 293–300.

Leatherbury, L., Gauldin, H. E., Waldo, K., & Kirby, M. L. (1990). Microcinephotography of the developing heart in neural crest-ablated chick embryos. Circulation, 81(3), 1047–1057.

Lepore, J. J., Mericko, P. A., Cheng, L., Lu, M. M., Morrisey, E. E., & Parmacek, M. S. (2006). GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis. The Journal of Clinical Investigation, 116(4), 929–939.

Liu, Y., Jin, Y., Li, J., Seto, E., Kuo, E., Yu, W., Schwartz, R. J., Blazo, M., Zhang, S. L., & Peng, X. (2013). Inactivation of Cdc42 in neural crest cells causes craniofacial and cardiovascular morphogenesis defects. Developmental Biology, 383(2), 239–252.

Manderfield, L. J., High, F. A., Engleka, K. A., Liu, F., Li, L., Rentschler, S., & Epstein, J. A. (2012). Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation, 125(2), 314–323.

Molin, D. G. M., Poelmann, R. E., DeRuiter, M. C., Azhar, M., Doetschman, T., & Gittenberger-de Groot, A. C. (2004). Transforming growth factor β-SMAD2 signaling regulates aortic arch innervation and development. Circulation Research, 95(11), 1109–1117.

Morishima, M., Yanagisawa, H., Yanagisawa, M., & Baldini, A. (2003). Ece1 and Tbx1 define distinct pathways to aortic arch morphogenesis. Developmental Dynamics : An Official Publication of the American Association of Anatomists, 228(1), 95–104.

Nie, X., Deng, C. xia, Wang, Q., & Jiao, K. (2008). Disruption of Smad4 in neural crest cells leads to mid-gestation death with pharyngeal arch, craniofacial and cardiac defects. Developmental Biology, 316(2), 417–430.

Plein, A., Fantin, A., & Ruhrberg, C. (2015). Neural crest cells in cardiovascular development. In Current Topics in Developmental Biology (1st ed., Vol. 111). Elsevier Inc.

Porras, D., & Brown, C. B. (2008). Temporal-spatial ablation of neural crest in the mouse results in cardiovascular defects. Developmental Dynamics : An Official Publication of the American Association of Anatomists, 237(1), 153–162.

Sato, M., Tsai, H. J., & Yost, H. J. (2006). Semaphorin3D regulates invasion of cardiac neural crest cells into the primary heart field. Developmental Biology, 298(1), 12–21.

Toyofuku, T., Yoshida, J., Sugimoto, T., Yamamoto, M., Makino, N., Takamatsu, H., Takegahara, N., Suto, F., Hori, M., Fujisawa, H., Kumanogoh, A., & Kikutani, H. (2008). Repulsive and attractive semaphorins cooperate to direct the navigation of cardiac neural crest cells. Developmental Biology, 321(1), 251–262.

Vallejo-Illarramendi, A., Zang, K., & Reichardt, L. F. (2009). Focal adhesion kinase is required for neural crest cell morphogenesis during mouse cardiovascular development. The Journal of Clinical Investigation, 119(8), 2218–2230.

Waldo, K. L., Hutson, M. R., Stadt, H. A., Zdanowicz, M., Zdanowicz, J., & Kirby, M. L. (2005). Cardiac neural crest is necessary for normal addition of the myocardium to the arterial pole from the secondary heart field. Developmental Biology, 281(1), 66–77.

Waldo, K. L., Kumiski, D., & Kirby, M. L. (1996). Cardiac neural crest is essential for the persistence rather than the formation of an arch artery. Developmental Dynamics, 205(3), 281–292.<281::AID-AJA8>3.0.CO;2-E

Wang, J., Nagy, A., Larsson, J., Dudas, M., Sucov, H. M., & Kaartinen, V. (2006). Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects. BMC Developmental Biology, 6.

Wurdak, H., Ittner, L. M., Lang, K. S., Leveen, P., Suter, U., Fischer, J. A., Karlsson, S., Born, W., & Sommer, L. (2005). Inactivation of TGFβ signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome. Genes and Development, 19(5), 530–535.

Yamagishi, H. (2021). Cardiac neural crest. Cold Spring Harbor Perspectives in Biology, 13(1), 1–18.