title: The spectrum of cardiovascular anomalies in CHF1/Hey2 deficient mice reveals roles in endocardial cushion, myocardial and vascular maturation.
abstract: CHF1/Hey2 null mice generated in different laboratories have discrepant cardiovascular phenotypes. To determine the effect of genetic background on phenotype, we backcrossed our knockout strain more than eight generations to the inbred strains BALB/c and C57BL/6. Knockout mice on these backgrounds showed disparate phenotypes. Mice on both backgrounds demonstrated ventricular septal defects (VSDs), tricuspid stenosis and mitral valve thickening, but at varying frequencies, suggesting a general defect in endocardial cushion remodeling. Additional defects seen exclusively on the C57BL/6 background included biventricular wall thinning and left ventricular enlargement, implying a more severe myocardial defect than previously observed. In addition, aortas and pulmonary arteries from these null mice had thinner walls. Intercrossing of the CHF1/Hey2 null mice on a C57BL/6 background with a C57BL/6 MLC2v-CHF1/Hey2 transgenic line overexpressing CHF1/Hey2 in the atrial and ventricular myocardium also rescued the VSD and myocardial phenotypes, but did not affect vascular wall thickness. Our results indicate that CHF1/Hey2 provides an important myocardial signal to the endocardial cushion for proper septation and valve formation and also plays an important role in maturation of the myocardium and vasculature.
authors.affiliation: Vascular Medicine Research, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Room 277, Cambridge, MA 02139, USA.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sakata
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Fan
authors.initials: F
authors.lastname: Xiang
authors.forename: Joey M
authors.initials: JM
authors.lastname: Youngblood
authors.forename: Caramai N
authors.initials: CN
authors.lastname: Kamei
authors.forename: Michael T
authors.initials: MT
authors.lastname: Chin
mesh_terms: D000818:Animals; D001011:Aorta / Q000002:abnormalities; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000235:genetics; D018376:Cardiovascular Abnormalities / Q000235:genetics*; D004694:Endocardial Cushion Defects / Q000235:genetics; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D006321:Heart / Q000254:growth & development; D006352:Heart Ventricles / Q000002:abnormalities; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008943:Mitral Valve / Q000002:abnormalities; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics; D014264:Tricuspid Valve Stenosis / Q000235:genetics; D017540:Tunica Media / Q000002:abnormalities
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C485778:Hey2 protein, mouse