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Relationship: 2562
Title
Disruption, Progenitor cells of second heart field leads to Reduced neural crest cell migration
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 | Moderate | Low | Gina Mennen (send email) | Open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
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
Evidence Supporting this KER
Biological Plausibility
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).
Empirical Evidence
The evidence for the relationship between SHF and cNCC is mainly studied by KO/ablation/hypomorphic/mutant studies, mainly in chick and mice and therefore the empirical evidence is low. Human with DiGeorge Syndrome show a plethora of phenotypes including cardiovascular malformations. Mouse models for DiGeorge syndrome indicate a crucial role for Tbx1 (Jerome & Papaioannou, 2001; Lindsay et al., 2001; Merscher et al., 2001; Ryckebusch et al., 2010; Vermot et al., 2003; Yutzey, 2010).
Tbx1 is expressed in the pharyngeal ectoderm, endoderm and the SHF in mice, but not in cNCCs (A. L. Keyte et al., 2014; Vitelli et al., 2002). Tbx1 loss specific to the pharyngeal mesoderm (SHF) can negatively impact cNCCs (Diman et al., 2011; Xu et al., 2004). This can result in migration of fewer cNCCs and defects in aorticopulmonary septation. When Tbx1 is mutated in mice, all-trans retinoic acid (ATRA) levels are upregulated (A. L. Keyte et al., 2014). ATRA is not only important in SHF patterning but also in cNCC morphogenesis and therefore a reduction in Tbx1 may affect the signaling between SHF and cNCCs, although other apparent interlineage signaling factors are observed as well (Neeb et al., 2013).
Fgf8 expression is also reduced when Tbx1 is mutated in mice (Vitelli et al., 2002). FGF8 hypomorphic and conditional mouse mutants, result in abnormal cNCC apoptosis and therefore possibly a reduced signaling to the cNCCs (Abu-Issa et al., 2002; A. L. Keyte et al., 2014). Overexpression of FGF8 results in a faster migration of a greater cNCCs number. So FGF8 affects cNCCs survival, timing and targeting (A. L. Keyte et al., 2014). Hypomorphs in Fgf8 show the cardiovascular developmental defects in the patterning of the aortic arch (AA), outflow tract (OFT) patterning, double outlet right ventricle (DORV), and persistent truncus arteriosus (PTA) in mice (Jain et al., 2010). Specific SHF Fgf8 mutants result in PTA, OFT, and DORV abnormalities and Nkx2.5-Cre specific Fgf8 deletion (in the broader cardiac expression domain) also included truncated heart tubes (Jain et al., 2010).
The evidence of Fgf8 expression being involved in cNCC stimulation and consequently cardiovascular development, seems to be of indirect nature. The direct effectors of Fgf8, the receptors Fgfr1 and Fgfr2 or the adaptor protein FRS2α, showed slightly different defects as compared to Fgf8 mutations and only ablations of these receptors in the SHF but not the endothelium or cNCCs, resulted in reduced SHF proliferation (Jain et al., 2010; Rochais et al., 2009). Therefore, likely an indirect signal to the NCCs is involved, such as through Bmp4, Sema3c, or Wnt signaling (Jain et al., 2010; Rochais et al., 2009).
In SHF specific Fgf8 mutants the BMP/TGFβ is affected that consequently perturbs cNCCs migration and development through Smad signaling (A. Keyte & Hutson, 2012; Nie et al., 2008; Park et al., 2008; Vincent & Buckingham, 2010). Nkx2-5-Cre specific Bmp4 deletion may also indicate the signaling factor from the SHF to cNCCs, as this resulted in perturbed OFT formation, interrupted AA, abnormal AA remodeling, and hypoplastic conotruncal cushions (Neeb et al., 2013). When deleting the Bmp receptors Alk2 and Alk3, this resulted in strikingly similar phenotypes as compared to FGF mutants (Jain et al., 2010). This phenomenon was also observed when Smad4 was conditionally deleted (Jain et al., 2010).
Fgf8 also affects Sema3C in cNCC. Sema3C is important in targeting migration of cNCCs which contain the Sema3C receptors PlexinA2, PlexinD1, and Neuropilin1 (Nrp1). Both PlexinA2 and Nrp1 knock-out mice show interrupted aortic arch (IAA) and persistent truncus arteriosus (PTA) associated with decreased cNCCs (Chin et al., 2012). Sema3C knock-out mice also show IAA and PTA (A. L. Keyte et al., 2014). Sema3c is stimulated through various factors. In hypomorph Tbx1 mice, Sema3c expression was inhibited in response to reduced Fgf8 expression. When blocking Fgf8 in chicken, this resulted in an ectopic expression of Sema3c and defects in cNCC migration (Kodo et al., 2017). Tbx1 thus regulates Sema3C, which is specifically required by cNCCs (A. L. Keyte et al., 2014). Foxc1/c2 also activates the transcription of Sema3c in the OFT. Gata6 mutation disturbs target genes expression levels including SEMA3C and PlexinA2 (Kodo et al., 2021).
An indirect effect of Fgf8 through Wnt could be possible as well (Jain et al., 2010; Rochais et al., 2009). Wnt5a is expressed in the SHF and Wnt5a mutants show DORV and abnormal invasion of NCCs (Rochais et al., 2009). However, these embryos didn’t show alterations in Fgf8, Fgf10 and Tbx1 gene expression levels. This suggests a signaling route from the SHF to cNCCs through noncanonical Wnt signaling. This was supported by the Fz2 receptor, which was transiently expressed in cardiac neural crest cells (Rochais et al., 2009).
Notch mediates Fgf8 signaling in the SHF (Jain et al., 2010). Notch interference correlates with a decreased Fgf8 and BMP signaling (High et al., 2009; Park et al., 2008). This is therefore indicative of an indirect effect (Vincent & Buckingham, 2010). In vivo effects of Notch interference in both the SHF or the NCCs resulted in abnormal arterial pole and arch artery phenotypes (High et al., 2007, 2008, 2009; High & Epstein, 2008; Vincent & Buckingham, 2010). The abnormal phenotypes of the OFT including PTA, DORV and AA patterning next to faulty cNCC migration were also observed in SHF deletion of Notch or Jagged1 (High et al., 2009; Jain et al., 2010; A. L. Keyte et al., 2014).
Uncertainties and Inconsistencies
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
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
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