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Relationship: 2562

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

Disruption, Progenitor cells of second heart field leads to Reduced neural crest cell migration

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 Moderate 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 Do not cite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

Interactions between the second heart field (SHF), pharyngeal endoderm and neural crest are needed for heart development and are interdependent. For this reason, the biological plausibility of this connection is moderate as in this KER the effects of impaired SHF patterning on cardiac neural crest cells (cNCC) functioning is addressed (Diman et al., 2011).

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

Migration of cNCCs from the neural tube through the pharyngeal arches to the cardiac progenitors is required for normal cardiovascular development. Additionally, the cNCCs need to be functional upon arrival. To stimulate this process, signaling molecules are necessary to attract and stimulate the cNCC for contributing to cardiovascular development. Keyte et al. reviewed the evolutionary relevance of cNCCs related to cardiovascular development and conclude that to all vertebrates a common SHF is evolved and the function of cNCCs could have very early roots in vertebrate evolution  (A. L. Keyte et al., 2014).

The importance of the SHF in relation to cardiovascular development is shown by ablation studies of SHF specific genes Isl1 and Mef2c which resulted in failed a proper development of heart tube elongation, looping, the right ventricle, the atria, and the OFT (C. L. Cai et al., 2003; Neeb et al., 2013).

It is unclear how different SHF subpopulations are involved in respect to cNCC migration and functioning, ablation of specific genes in the SHF/splanchnic mesoderm show defects in cNCC migration and/or functioning. For example, Tbx1 acts mainly in the anterior SHF during normal cardiovascular development and is involved in pharyngeal arch development, which involve formation of the outflow tract (OFT), right ventricle and the aortic arch (Nakajima, 2019). Tbx1 expression is highly conserved in pharyngeal arches of vertebrates (A. L. Keyte et al., 2014). Semaphorin 3C (Sem3C) is also expressed in a subdomain of the SHF, indicates for pulmonary trunk myocardium, and is necessary for NC migration to the hearts’ arterial pole (Vincent & Buckingham, 2010). The cNCC expresses Sem3C receptors PlexinD1 and PlexinA2, which are required for correct OFT development (Vincent & Buckingham, 2010). The protein FGF8 is expressed at high levels in the pharyngeal ectoderm and endoderm adjacent to the cNCC migratory pathway, and at lower levels in the splanchnic mesoderm (SHF) and is a chemoattractant for cNCCs (Hutson et al. 2006; Sato et al. 2011).

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

The migration and development of cNCCs not solely depends on SHF signaling. The pharyngeal endoderm also plays an important role in the maintenance and deployment of cNCCs through signaling of sonic hedgehog (Shh) (Goddeeris et al., 2007; Vincent & Buckingham, 2010). In the absence of Shh, the development of proper pharyngeal arches and OFT is affected (Vincent & Buckingham, 2010). Additionally, a possible feedback loop exists between SHF signaling to cNCCs, since ablation of cNCCs results in SHF overproliferation because of excessive Fgf8 signaling (Rochais et al., 2009). Furthermore, NCC deletion of Smad4 leads to abnormal SHF patterning and a shorter OFT. Lastly, Tbx3 loss in NCCs and pharyngeal endoderm also resulted in SHF overproliferation and a shorter OFT (Rochais et al., 2009).

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

Abu-Issa, R., Smyth, G., Smoak, I., Yamamura, K. I., & Meyers, E. N. (2002). Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development, 129(19), 4613–4625. https://doi.org/10.1242/dev.129.19.4613

Cai, C. L., Liang, X., Shi, Y., Chu, P. H., Pfaff, S. L., Chen, J., & Evans, S. (2003). Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Developmental Cell, 5(6), 877–889. https://doi.org/10.1016/S1534-5807(03)00363-0

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. https://doi.org/10.1016/J.MOD.2012.05.005

Diman, N. Y. S. G., Remacle, S., Bertrand, N., Picard, J. J., Zaffran, S., & Rezsohazy, R. (2011). A retinoic acid responsive Hoxa3 transgene expressed in embryonic pharyngeal endoderm, cardiac neural crest and a subdomain of the second heart field. PloS One, 6(11). https://doi.org/10.1371/JOURNAL.PONE.0027624

Goddeeris, M. M., Schwartz, R., Klingensmith, J., & Meyers, E. N. (2007). Independent requirements for Hedgehog signaling by both the anterior heart field and neural crest cells for outflow tract development. Development (Cambridge, England), 134(8), 1593–1604. https://doi.org/10.1242/DEV.02824

High, F. A., & Epstein, J. A. (2008). The multifaceted role of Notch in cardiac development and disease. Nature Reviews. Genetics, 9(1), 49–61. https://doi.org/10.1038/NRG2279

High, F. A., Jain, R., Stoller, J. Z., Antonucci, N. B., Min, M. L., Loomes, K. M., Kaestner, K. H., Pear, W. S., & Epstein, J. A. (2009). Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development. Journal of Clinical Investigation, 119(7), 1986–1996. https://doi.org/10.1172/JCI38922

High, F. A., Min, M. L., Pear, W. S., Loomes, K. M., Kaestner, K. H., & Epstein, J. A. (2008). Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proceedings of the National Academy of Sciences of the United States of America, 105(6), 1955–1959. https://doi.org/10.1073/PNAS.0709663105

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. https://doi.org/10.1172/JCI30070

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. https://doi.org/10.1111/j.1749-6632.2009.05099.x

Jerome, L. A., & Papaioannou, V. E. (2001). DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genetics, 27(3), 286–291. https://doi.org/10.1038/85845

Keyte, A., & Hutson, M. R. (2012). The neural crest in cardiac congenital anomalies. Differentiation, 84(1), 25–40. https://doi.org/10.1016/j.diff.2012.04.005

Keyte, A. L., Alonzo-Johnsen, M., & Hutson, M. R. (2014). Evolutionary and developmental origins of the cardiac neural crest: Building a divided outflow tract. Birth Defects Research Part C - Embryo Today: Reviews, 102(3), 309–323. https://doi.org/10.1002/BDRC.21076

Kodo, K., Shibata, S., Miyagawa-Tomita, S., Ong, S. G., Takahashi, H., Kume, T., Okano, H., Matsuoka, R., & Yamagishi, H. (2017). Regulation of Sema3c and the Interaction between Cardiac Neural Crest and Second Heart Field during Outflow Tract Development. Scientific Reports, 7(1). https://doi.org/10.1038/S41598-017-06964-9

Kodo, K., Uchida, K., & Yamagishi, H. (2021). Genetic and Cellular Interaction During Cardiovascular Development Implicated in Congenital Heart Diseases. Frontiers in Cardiovascular Medicine, 8. https://doi.org/10.3389/FCVM.2021.653244

Lindsay, E. A., Vitelli, F., Su, H., Morishima, M., Huynh, T., Pramparo, T., Jurecic, V., Ogunrinu, G., Sutherland, H. F., Scambler, P. J., Bradley, A., & Baldini, A. (2001). Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature, 410(6824), 97–101. https://doi.org/10.1038/35065105

Merscher, S., Funke, B., Epstein, J. A., Heyer, J., Puech, A., Lu, M. M., Xavier, R. J., Demay, M. B., Russell, R. G., Factor, S., Tokooya, K., Jore, B. S., Lopez, M., Pandita, R. K., Lia, M., Carrion, D., Xu, H., Schorle, H., Kobler, J. B., … Kucherlapati, R. (2001). TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell, 104(4), 619–629. https://doi.org/10.1016/S0092-8674(01)00247-1

Nakajima, Y. (2019). Retinoic acid signaling in heart development. Genesis, 57(7). https://doi.org/10.1002/dvg.23300

Neeb, Z., Lajiness, J. D., Bolanis, E., & Conway, S. J. (2013). Cardiac outflow tract anomalies. Wiley Interdisciplinary Reviews. Developmental Biology, 2(4), 499–530. https://doi.org/10.1002/WDEV.98

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. https://doi.org/10.1016/J.YDBIO.2008.02.006

Park, E. J., Watanabe, Y., Smyth, G., Miyagawa-Tomita, S., Meyers, E., Klingensmith, J., Camenisch, T., Buckingham, M., & Moon, A. M. (2008). An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart. Development, 135(21), 3599–3610. https://doi.org/10.1242/DEV.025437

Rochais, F., Mesbah, K., & Kelly, R. G. (2009). Signaling pathways controlling second heart field development. Circulation Research, 104(8), 933–942. https://doi.org/10.1161/CIRCRESAHA.109.194464

Ryckebusch, L., Bertrand, N., Mesbah, K., Bajolle, F., Niederreither, K., Kelly, R. G., & Zaffran, S. (2010). Decreased levels of embryonic retinoic acid synthesis accelerate recovery from arterial growth delay in a mouse model of DiGeorge syndrome. Circulation Research, 106(4), 686–694. https://doi.org/10.1161/CIRCRESAHA.109.205732

Vermot, J., Niederreither, K., Garnier, J. M., Chambon, P., & Dollé, P. (2003). Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice. Proceedings of the National Academy of Sciences of the United States of America, 100(4), 1763–1768. https://doi.org/10.1073/pnas.0437920100

Vincent, S. D., & Buckingham, M. E. (2010). How to make a heart. The origin and regulation of cardiac progenitor cells. Current Topics in Developmental Biology, 90(C), 1–41. https://doi.org/10.1016/S0070-2153(10)90001-X

Vitelli, F., Morishima, M., Taddei, I., Lindsay, E. A., & Baldini, A. (2002). Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Human Molecular Genetics, 11(8), 915–922. https://doi.org/10.1093/HMG/11.8.915

Xu, H., Morishima, M., Wylie, J. N., Schwartz, R. J., Bruneau, B. G., Lindsay, E. A., & Baldini, A. (2004). Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development (Cambridge, England), 131(13), 3217–3227. https://doi.org/10.1242/DEV.01174

Yutzey, K. E. (2010). Digeorge syndrome, Tbx1, and retinoic acid signaling come full circle. Circulation Research, 106(4), 630–632. https://doi.org/10.1161/CIRCRESAHA.109.215319