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WIREs Dev Biol
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Cardiac outflow tract anomalies

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Abstract The mature outflow tract (OFT) is, in basic terms, a short conduit. It is a simple, although vital, connection situated between contracting muscular heart chambers and a vast embryonic vascular network. Unfortunately, it is also a focal point underlying many multifactorial congenital heart defects (CHDs). Through the use of various animal models combined with human genetic investigations, we are beginning to comprehend the molecular and cellular framework that controls OFT morphogenesis. Clear roles of neural crest cells (NCC) and second heart field (SHF) derivatives have been established during OFT formation and remodeling. The challenge now is to determine how the SHF and cardiac NCC interact, the complex reciprocal signaling that appears to be occurring at various stages of OFT morphogenesis, and finally how endocardial progenitors and primary heart field (PHF) communicate with both these colonizing extra‐cardiac lineages. Although we are beginning to understand that this dance of progenitor populations is wonderfully intricate, the underlying pathogenesis and the spatiotemporal cell lineage interactions remain to be fully elucidated. What is now clear is that OFT alignment and septation are independent processes, invested via separate SHF and cardiac neural crest (CNC) lineages. This review will focus on our current understanding of the respective contributions of the SHF and CNC lineage during OFT development and pathogenesis. WIREs Dev Biol 2013, 2:499–530. doi: 10.1002/wdev.98 This article is categorized under: Birth Defects > Organ Anomalies

Schematics of the four major structural outflow tract (OFT) defects. Simplified illustration of a normal heart and OFT, including separate aorta (A) and pulmonary trunks (P), that exit the fully divided left (LV) and right ventricles (RV) respectively. Persistent truncus arteriosus (PTA), in which there is only a single undivided OFT exiting the RV of the heart. The blood exits the LV via an interventricular septal defect (VSD), indicated via broken line between RV and LV. Double outlet right ventricle (DORV), in which the divided aorta (A) and pulmonary trunks (P) both exit the RV only and the interventricular septum fails to close resulting in a VSD. Transposition of the great arteries (TGA), in which the aorta (A) and pulmonary trunks (P) are fully septated, but the aorta arises from the RV and the pulmonary trunk arises from the LV. Overriding aorta (OA) where the aorta is positioned directly over a VSD, instead of over the LV.

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Isl1Cre is functionally expressed in migrating neural crest cells (NCC). Using intersectional fate mapping via Isl1Cre and Wnt1‐Flpe along with the RC::FrePe indicator mouse line (which reports dual Flpe and Cre recombination), it has been recently demonstrated that some Isl1 derivatives in the cardiac outflow tract (OFT) can derive from Wnt1‐expressing NCC. (a) RC::FrePe mouse embryos positive for Wnt1‐Flpe develop normally, and when Isl1Cre lineage is fate mapped using mCherry red fluorescence, NCC migrating into the craniofacial region maintain mCherry fluorescence in the absence of Isl1Cre expression (b, arrowhead). Additionally, Wnt1‐Flpe mapped NCC‐derived dorsal root ganglia (DRGs) demonstrate eGFP fluorescence (c, arrows). However, cardiac neural crest (CNC) populating the OFT cushions demonstrate both mCherry (d) and eGFP (e) fluorescence suggesting that some (but certainly not all) of Wnt1‐Flpe marked CNC populating the OFT endocardial cushions have expressed Isl1Cre at some time earlier. (Reprinted with permission from Ref 187. Copyright 2012 Wolters Kluwer Health)

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FGF signaling within the Isl1Cre lineage critical for outflow tract (OFT) morphogenesis. Deletion of the sequences that code for the ‘c’ isoforms of FGFR1 and FGFR2 in double heterozygote mice demonstrate grossly (a,b) normal OFT rotation, septation, and orientation. However, Isl1Cre‐conditional Fgfr1c and 2c isoform mutants demonstrate double outlet right ventricle (DORV) (c,d) and PTA (e,f). Histological analysis confirmed that OFT develop normally in Fgfr1c/Fgfr2c double heterozygote mice (b), but that combined conditional ablation of Fgfr1c and Fgfr2c isoforms results in OFT defects including DORV (d) and type‐I persistent truncus arteriosus (PTA) (f). Ao, aorta; co, conus; PA, pulmonary artery; RV, right ventricle; TA, truncus arteriosus. (Reprinted with permission from Ref Copyright 2008 The Company of Biologists Ltd)

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Reduced neural crest cells (NCC) emigration and migration in mice embryos lacking Pax3 expression. Dorsal (a) and left lateral (b) views of E9.0 Pax3Δ5 null embryos (a and b, right) demonstrate decreased NCC emigration and migration toward the second PA (indicated by *), when compared to wild‐type littermates (a and b, left). First pharyngeal arch and cranial NCC migration are unaffected in Pax3Δ5 nulls. (c) Right lateral views of E9.5 demonstrate that fewer CNC populate the heterozygous third, fourth, and sixth pulmonary artery (PAs) (c, middle embryo), and still even less cardiac neural crest (CNC) colonize the Pax3 null 3/4/6th arches (c, right embryo indicated by white *) compared to wild‐type littermates (c, left). Cranial NCC migration is unaffected by loss of Pax3. (d,e) Histology of Pax3Δ5 null embryos demonstrated a lack of Wnt1Cre‐marked CNC within the fourth PA (d), AP septum (indicated by * in wild‐type in e), and OFT cushions compared to wild‐type controls. (Reprinted with permission from Ref Copyright 2011 Elsevier Ltd)

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Bmp4 expression in Mef2cCre expressing cells is necessary for outflow tract (OFT) septation. Transgenic Mef2c‐Cre is expressed in second heart field (SHF)‐derived structures of the right heart and OFT (b and c). Bmp4 is expressed in the pharengeal ectoderm (d) and OFT myocardium (e). Conditional ablation of Bmp4 in Mef2c‐Cre expressing cells reduces Bmp4 expression in OFT myocardium (g) and results in persistent truncus arteriosus (PTA). (Reprinted with permission from Ref 196. Copyright 2008 John Wiley and Sons).

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Genesis of the OFT. (a,b) E9.5 mouse embryo illustrating origin (black outline) and migration pathways of CNC (blue in a) to OFT truncal cushions and SHF (red in b) to OFT myocardial cuff and overlying endocardial cells within truncal region. (c) Schematic shows the locations of OFT colonization by the extra‐cardiac CNC (blue), SHF (red) and the location of the EMT‐derived conal endocardial cushions (green). Additionally, the position of the aorticopulmonary septum is indicated by * symbol. a, atria; AS, aortic sac; AVC, aorto‐ventricular cushions; otic, otic placode; optic, optic placode, 1–6, first to sixth aortic arches; LV left ventricle; RV, right ventricle.

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Genetic neural crest cells (NCC) ablation in Wnt1‐Cre;R26‐EGFP‐DTA embryos results in gross morphological defects including persistent truncus arteriosus (PTA). Gross examination under UV light demonstrates lack of craniofacial structures (a, open arrowhead) and internalized eyes following genetic NCC ablation in Wnt1‐Cre;R26‐EGFP‐DTA embryos (a) compared to R26‐EGFP‐DTA alone (b) and littermates lacking the transgene (c) at E15 (with brightfield insets). Subsequent transverse sectioning and counterstaining with αSMA immunohistochemistry (brown DAB staining) demonstrates reduced outflow tract (OFT) smooth muscle cells surrounding a grossly abnormal heart and OFT with PTA in Wnt1‐Cre;R26‐EGFP‐DTA embryos (d) compared to normal OFT morphogenesis in R26‐EGFP‐DTA controls (e). Note that PTA OFT has four valve leaflets (indicated by * in d) compared to two normal pulmonary leaflets in normal hearts (indicated by * in e). Panels (f) and (g) illustrate the associated interventricular septal defects Wnt1‐Cre;R26‐EGFP‐DTA embryos with OFT defects (f) compared to closed septum between left and right ventricles in control (g) embryos. (Reprinted with permission from Ref Copyright 2011 Elsevier Ltd)

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