title: Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development.
abstract: Lipoprotein-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 ofLrp2knockout (KO) mice have not yet been investigated. We studied the cardiovascular development ofLrp2KO 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. TheLrp2KO 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 theLrp2KO. 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 withLRP2mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Baardman
authors.affiliation: Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Mathijs V
authors.initials: MV
authors.lastname: Zwier
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, PO-Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Lambertus J
authors.initials: LJ
authors.lastname: Wisse
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, PO-Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Gittenberger-de Groot
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Wilhelmina S
authors.initials: WS
authors.lastname: Kerstjens-Frederikse
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center Rotterdam, PO-Box 2040, Rotterdam 3000 CA, The Netherlands Neural Development and Gastroenterology Units, UCL Institute of Child Health, London WC1 NEH, UK.
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.affiliation: Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Angelika
authors.initials: A
authors.lastname: Jurdzinski
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, PO-Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Beerend P
authors.initials: BP
authors.lastname: Hierck
authors.affiliation: Department of Cardiology and Department of Anatomy and Embryology, Leiden University Medical Center, PO-Box 9600, Leiden 2300 RC, The Netherlands.
authors.forename: Monique R M
authors.initials: MR
authors.lastname: Jongbloed
authors.affiliation: Center for Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Rolf M F
authors.initials: RM
authors.lastname: Berger
authors.affiliation: Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Torsten
authors.initials: T
authors.lastname: Plösch
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, PO-Box 9600, Leiden 2300 RC, The Netherlands m.c.deruiter@lumc.nl.
authors.forename: Marco C
authors.initials: MC
authors.lastname: DeRuiter
mesh_terms: D000818:Animals; D002465:Cell Movement; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D004730:Endothelium, Vascular / Q000196:embryology / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000473:pathology*; D006352:Heart Ventricles / Q000196:embryology / Q000473:pathology; D021621:Imaging, Three-Dimensional; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009206:Myocardium / Q000473:pathology; D009432:Neural Crest / Q000473:pathology; D010496:Pericardium / Q000196:embryology / Q000473:pathology
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse
keywords: Cardiac outflow tract; Heart development; Lipoprotein-related receptor protein 2; Neural crest; Second heart field
references.citation: Dev Biol. 2001 Jul 1;235(1):62-73
references.pmid: 11412027
references.citation: Nature. 2015 May 28;521(7553):520-4
references.pmid: 25807483
references.citation: Dev Biol. 2001 Oct 1;238(1):97-109
references.pmid: 11783996
references.citation: Mech Dev. 2002 Sep;117(1-2):115-22
references.pmid: 12204252
references.citation: Pediatr Nephrol. 2002 Dec;17(12):993-9
references.pmid: 12478347
references.citation: J Cell Sci. 2003 Mar 15;116(Pt 6):955-60
references.pmid: 12584240
references.citation: Birth Defects Res A Clin Mol Teratol. 2003 Mar;67(3):149-53
references.pmid: 12797454
references.citation: Science. 2004 Sep 10;305(5690):1619-22
references.pmid: 15361625
references.citation: APMIS. 1988 May;96(5):379-94
references.pmid: 3288247
references.citation: Genomics. 1994 Jul 1;22(1):88-93
references.pmid: 7959795
references.citation: Development. 1994 Nov;120(11):3289-99
references.pmid: 7720568
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8460-4
references.pmid: 8710893
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8612-7
references.pmid: 8710919
references.citation: Circ Res. 1998 Jun 1;82(10):1043-52
references.pmid: 9622157
references.citation: Dev Dyn. 1998 Jul;212(3):373-84
references.pmid: 9671941
references.citation: Development. 1999 May;126(9):1845-57
references.pmid: 10101119
references.citation: J Am Soc Nephrol. 1999 Apr;10(4):685-95
references.pmid: 10203351
references.citation: J Pediatr. 1964 Feb;64:210-7
references.pmid: 14119520
references.citation: Development. 2005 Jan;132(2):405-14
references.pmid: 15623804
references.citation: Circ Res. 2005 Mar 18;96(5):526-34
references.pmid: 15705966
references.citation: Dev Biol. 2005 May 1;281(1):66-77
references.pmid: 15848389
references.citation: Cell. 2005 Sep 9;122(5):751-62
references.pmid: 16143106
references.citation: Gene Expr Patterns. 2005 Dec;6(1):69-78
references.pmid: 16027047
references.citation: Am J Clin Nutr. 2005 Dec;82(6):1155-61
references.pmid: 16332646
references.citation: Circ Res. 2006 Feb 17;98(3):421-8
references.pmid: 16397144
references.citation: Dev Biol. 2006 Aug 15;296(2):279-97
references.pmid: 16828734
references.citation: Nat Genet. 2007 Aug;39(8):957-9
references.pmid: 17632512
references.citation: Development. 2008 Mar;135(6):1179-87
references.pmid: 18272595
references.citation: Cell Metab. 2008 Mar;7(3):258-68
references.pmid: 18316031
references.citation: Dev Biol. 2008 Apr 15;316(2):524-37
references.pmid: 18328475
references.citation: Birth Defects Res A Clin Mol Teratol. 2009 Jan;85(1):76-81
references.pmid: 19089858
references.citation: Am J Med Genet A. 2009 Nov;149A(11):2457-63
references.pmid: 19839040
references.citation: Dev Biol. 2009 Dec 15;336(2):137-44
references.pmid: 19835857
references.citation: J Clin Invest. 2011 Jan;121(1):422-30
references.pmid: 21157040
references.citation: Biochim Biophys Acta. 2012 Jan;1821(1):99-112
references.pmid: 21704730
references.citation: Dev Biol. 2012 Jan 15;361(2):377-91
references.pmid: 22119054
references.citation: Dev Biol. 2012 Jun 15;366(2):111-24
references.pmid: 22546693
references.citation: Cardiovasc Res. 2012 Jul 1;95(1):108-15
references.pmid: 22499773
references.citation: Differentiation. 2012 Jul;84(1):25-40
references.pmid: 22595346
references.citation: Differentiation. 2012 Jul;84(1):41-53
references.pmid: 22652098
references.citation: Dev Dyn. 2012 Sep;241(9):1413-22
references.pmid: 22826212
references.citation: Hum Mol Genet. 2013 Jan 15;22(2):300-12
references.pmid: 23077214
references.citation: Biol Reprod. 2013 Jan;88(1):24
references.pmid: 23153566
references.citation: Circ Res. 2000 Nov 24;87(11):969-71
references.pmid: 11090540
references.citation: Development. 2001 Apr;128(7):1019-31
references.pmid: 11245568
references.citation: Circulation. 2001 Jun 5;103(22):2745-52
references.pmid: 11390347
references.citation: Ann Med. 2014 Dec;46(8):640-52
references.pmid: 25307363
references.citation: Development. 2001 Aug;128(16):3179-88
references.pmid: 11688566