Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development.

Maria E Baardman,Wilhelmina S Kerstjens-Frederikse,Marco C Deruiter,Monique R M Jongbloed,Angelika Jurdzinski,Beerend P Hierck,Rolf M F Berger,Adriana C Gittenberger- De Groot,Mathijs V Zwier,Robert M W Hofstra,Lambertus J Wisse,Torsten Plösch

doi:10.1242/dmm.022053

Abstract

ABSTRACTLipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascular development of Lrp2 KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. The Lrp2 KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.

Highlights

Lipoprotein-related receptor protein 2 (LRP2), known as megalin, is a transmembrane glycoprotein receptor on the surface of epithelial cells, and belongs to the low-density-lipoprotein receptor (LDLR) family
LRP2 is crucial for embryonic development in mice and humans and a role has been mentioned in the NCCs (Spoelgen et al, 2005) and in sonic hedgehog (Shh) signaling (McCarthy and Argraves, 2003), but a thorough analysis in cardiac development is lacking
Absence of LRP2 resulted in outflow tract (OFT) anomalies (CAT, aortic arch and coronary artery anomalies), ventricular septal defects and overriding of the tricuspid valve as well as a marked reduction of the compact layer of the ventricular myocardium, epicardial blebbing and the presence of deep intertrabecular spaces

Summary

Introduction

Lipoprotein-related receptor protein 2 (LRP2), known as megalin, is a transmembrane glycoprotein receptor on the surface of epithelial cells, and belongs to the low-density-lipoprotein receptor (LDLR) family. LRP2 is highly expressed throughout development, starting in the eight-cell stage, and is limited to the trophectoderm in the blastocyst stage (Assemat et al, 2005). After implantation, it is expressed on the maternal-fetal interface, including in the trophectoderm, the visceral endoderm of the yolk sac and the placenta (Gueth-Hallonet et al, 1994). LRP2 is a low-density lipoprotein (LDL) receptor on the yolk sac and placenta, and is involved in cholesterol transport as a co-transporter with cubilin (Christensen and Verroust, 2002)

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