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Heart defects in connexin43-deficient mice
J Ya1, E B Erdtsieck-Ernste, P A de Boer
1Department of Anatomy and Embryology, Academic Medical Center, University of Amsterdam, The Netherlands.
Insights
Connexin43 (CX43) disruption retards embryonic heart looping, causing malformations at the right ventricle and outflow tract junction. This leads to abnormal development, including intertrabecular pouches, impacting cardiac structure.
Area of Science:
- Developmental Biology
- Cardiovascular Research
- Genetics
Background:
- Connexin43 (CX43) is crucial for cardiac development, but its role in specific malformations is not fully understood.
- CX43 expression is widespread in the heart, yet cardiac malformations in CX43-disrupted mice are localized.
Purpose of the Study:
- To investigate the impact of connexin43 (CX43) disruption on cardiac morphogenesis.
- To identify the specific cardiac structures affected by CX43 deficiency during embryonic development.
Main Methods:
- Analysis of CX43-deficient mouse embryos from embryonic day 10 to birth.
- Utilized immunohistochemistry, hybridohistochemistry, and 3D reconstruction of serial heart sections.
Main Results:
- CX43 deficiency markedly retards the D-configuration of the embryonic heart's ascending loop.
- Abnormalities include a persistent craniomedial position of the right ventricle and an acute angle with the outflow tract.
- Delayed looping leads to a "crisscross" configuration and excessive development of intertrabecular pouches at the right ventricle-outflow tract junction.
Conclusions:
- Retarded D-loop formation in CX43-deficient hearts predisposes the right ventricle-outflow tract junction to malformations.
- These malformations include abnormal septation and the development of intertrabecular pouches, potentially affecting tricuspid valve development.
Abstract:
Cardiac malformation in connexin43 (CX43)-disrupted mice is restricted to the junction between right ventricle and outflow tract, even though CX43 is also expressed abundantly elsewhere. We analyzed cardiac morphogenesis in immunohistochemically and hybridohistochemically stained and three-dimensionally reconstructed serial sections of CX43-deficient embryos between embryonic day (ED) 10 and birth. The establishment of the D configuration in the ascending loop of CX43-deficient hearts is markedly retarded, so that the right ventricle retains a craniomedial position and is connected with the outflow tract by a more acute bend in ED10 and ED11 embryos. Because of the subsequent growth of the right ventricle, this condition usually evolves into a D loop, but when it persists, a "crisscross" configuration develops, with the atrioventricular cushions rotated 90 degrees, a horizontal muscular ventricular septum, and a parallel course of the endocardial ridges of the outflow tract. After ED12, large intertrabecular pouches develop at the ventricular side of both shelflike myocardial structures that support the endocardial ridges of the outflow tract, ie, at the location that was earlier characterized by the acute bend between the right ventricle and the outflow tract and that subsequently develops into the anterosuperior leaflet of the tricuspid valve. Retarded development of the D configuration in the ascending loop of the embryonic heart predisposes the myocardium at the junction of the right ventricle and outflow tract to excessive development of intertrabecular pouches during subsequent development.