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Relationship: 2563


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

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

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 Do not cite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

Sex Applicability

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

Life Stage Applicability

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

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

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 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 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
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

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).

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
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


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