Progressive Anatomical Closure of Foramen Ovale in Normal Neonatal Mouse Hearts

Cole‐Jeffrey, Colleen T.; Terada, Ryota; Neth, Matthew R.; Wessels, Andy; Kasahara, Hideko

doi:10.1002/ar.22432

Cited by 17 publications

(16 citation statements)

References 18 publications

(29 reference statements)

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“…We did not assess atrial septal anomalies in P1 mice, because all the mice, including wild-type controls demonstrate interatrial communications during the transition from the embryonic circulation, when right-to-left shunting of blood through the foramen ovale remains essential 36 . In FVB mice, such morphological closure of the inter-atrial communication is progressive, and is completed 1 week after birth 36 .…”

Section: Resultsmentioning

confidence: 99%

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A Mouse Model of Human Congenital Heart Disease

Ashraf

Pradhan

Chang

et al. 2014

Circ Cardiovasc Genet

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Background Heterozygous human mutations of NKX2-5 are highly penetrant and associated with varied congenital heart defects. The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy between human and mouse genetics. Since missense mutations in the NKX2-5 homeodomain (DNA binding domain) are the most frequently reported type of human mutation, we replicated this genetic defect in a murine knock-in model. Methods and Results We generated a murine model in a 129/Sv genetic background by knocking-in an Nkx2-5 homeodomain missense mutation previously identified in humans. The mutation was located at homeodomain position 52Arg→Gly (R52G). All the heterozygous neonatal Nkx2-5+/R52G mice demonstrated a prominent trabecular layer in the ventricular wall, so called noncompaction, along with diverse cardiac anomalies, including atrioventricular septal defects, Ebstein’s malformation of the tricuspid valve, and perimembranous and/or muscular ventricular septal defects. In addition, P10 Nkx2-5+/R52G mice demonstrated atrial septal anomalies, with significant increase in the size of the inter-atrial communication and fossa ovalis, and decrease in the length of the flap valve compared to control Nkx2-5+/+ or Nkx2-5+/− mice. Conclusion The results of our study demonstrate that heterozygous missense mutation in the murine Nkx2-5 homeodomain (R52G) are highly penetrant, and result in pleiotropic cardiac effects. Thus, in contrast to heterozygous Nkx2-5 knockout mice, the effects of the heterozygous knock-in mimic findings in humans with heterozygous missense mutation in NKX2-5 homeodomain.

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Section: Resultsmentioning

confidence: 99%

“…In FVB mice, such morphological closure of the inter-atrial communication is progressive, and is completed 1 week after birth 36 . In 129/Sv mice, in contrast, half of the wild-type mice still demonstrated small interatrial communications, with an average size of ~40 μm (8 serial sections, 5 μm thickness) at P10 (n=10).…”

Section: Resultsmentioning

confidence: 99%

A Mouse Model of Human Congenital Heart Disease

Ashraf

Pradhan

Chang

et al. 2014

Circ Cardiovasc Genet

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“…F). In smaller mammals, such as mouse and rat, closure of the foramen ovale occurs in the first week, whereas it takes months in cattle (Murakami et al, ; Cole‐Jeffrey et al, ; Elliott et al, ). The closure in rat is due to fibrosis mediated by transition of the endocardium into mesenchyme of the primary and secondary septum (Elliott et al, ).…”

Section: Normal Development Of the Atrial Septum In Eutherian Mammalsmentioning

confidence: 99%

Evolution and Development of the Atrial Septum

Jensen

Wang

Moorman

2018

The Anatomical Record

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The complete division of the atrial cavity by a septum, resulting in a left and right atrium, is found in many amphibians and all amniotes (reptiles, birds, and mammals). Surprisingly, it is only in eutherian, or placental, mammals that full atrial septation necessitates addition from a second septum. The high incidence of incomplete closure of the atrial septum in human, so‐called probe patency, suggests this manner of closure is inefficient. We review the evolution and development of the atrial septum to understand the peculiar means of forming the atrial septum in eutherian mammals. The most primitive atrial septum is found in lungfishes and comprises a myocardial component with a mesenchymal cap on its leading edge, reminiscent to the primary atrial septum of embryonic mammals before closure of the primary foramen. In reptiles, birds, and mammals, the primary foramen is closed by the mesenchymal tissues of the atrioventricular cushions, the dorsal mesenchymal protrusion, and the mesenchymal cap. These tissues are also found in lungfishes. The closure of the primary foramen is preceded by the development of secondary perforations in the septal myocardium. In all amniotes, with the exception of eutherian mammals, the secondary perforations do not coalesce to a secondary foramen. Instead, the secondary perforations persist and are sealed by myocardial and endocardial growth after birth or hatching. We suggest that the error‐prone secondary foramen allows large volumes of oxygen‐rich blood to reach the cardiac left side, needed to sustain the growth of the extraordinary large offspring that characterizes eutherian mammals. Anat Rec, 302:32–48, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

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“…A series of recently published studies, however, indicate that abnormal development of tissues derived from the Second Heart Field (SHF), including the primary atrial septum and the Dorsal Mesenchymal Protrusion (DMP), may also play a role in the pathogenesis of these defects 6–14 .…”

Section: Introductionmentioning

confidence: 99%

Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation

Briggs

Phelps

Brown

et al. 2013

Circulation Research

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Rationale The Dorsal Mesenchymal Protrusion (DMP) is a prong of mesenchyme derived from the Second Heart Field (SHF) located at the venous pole of the developing heart. Recent studies have shown that perturbation of its development is associated with the pathogenesis of atrioventricular septal defect (AVSD). Although the importance of the DMP to AV septation is now established, the molecular and cellular mechanisms underlying its development are far from fully understood. Prior studies have demonstrated that bone morphogenetic protein (BMP) signaling is essential for proper formation of the AV endocardial cushions and the cardiac outflow tract. A role for BMP signaling in regulation of DMP development remained to be elucidated. Objective To determine the role of BMP signaling in DMP development. Methods and Results Conditional deletion of the BMP receptor Alk3 from venous pole SHF cells leads to impaired formation of the DMP and a completely penetrant phenotype of ostium primum defect, a hallmark feature of AVSDs. Analysis of mutants revealed decreased proliferative index of SHF cells and, consequently, reduced number of SHF cells at the cardiac venous pole. In contrast, volume and expression of markers associated with proliferation and active BMP/TGFβ signaling was not significantly altered in the AV cushions of SHF-Alk3 mutants. Conclusions BMP signaling is required for expansion of the SHF-derived DMP progenitor population at the cardiac venous pole. Perturbation of Alk3-mediated BMP signaling from the SHF results in impaired development of the DMP and ostium primum defects.

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Progressive Anatomical Closure of Foramen Ovale in Normal Neonatal Mouse Hearts

Cited by 17 publications

References 18 publications

A Mouse Model of Human Congenital Heart Disease

A Mouse Model of Human Congenital Heart Disease

Evolution and Development of the Atrial Septum

Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation

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