Mouse Genome Informatics
hm1
    Cyr61tm1Lfl/Cyr61tm1Lfl
involves: 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• only a few embryonic survivors developed to term and were born alive, but these mice died within 24 hours of birth
• homozygous null embryos were fully represented at E9.5, suggesting that implantation had proceeded normally
• however, at E9.5, some homozygous null embryos were already moribund; ~30% of null embryos died by E10.5 due to a failure in chorioallantoic fusion
• >70% of mutant embryos analyzed between E11.5 and E14.5 died from hemorrhage and/or placental defects of varying degrees of severity

embryogenesis
• at E11.5, approximately 70% of homozygous null embryos displayed successful chorioallantoic fusion but showed vascular deficiency in the chorionic plate, resulting in a relatively pale placenta
• at E12.5, histological analysis revealed vessel branches in the chorionic plate of wild-type but not homozygous null placenta
• both wild-type and null placentae developed differentiated zones, including the chorionic plate, the labyrinth, and the spongiotrophoblast layer adjacent to the maternal decidua
• homozygous null embryos displayed a specific defect in vessel bifurcation at the chorioallantoic junction, leading to severe undervascularization in the placental labyrinth
• unlike the wild-type labyrinth, the mutant labyrinth was saturated with maternal blood sinuses and few fetal vessels were detected
• notably, trophoblast nuclei were evident in both wild-type and mutant labyrinth, and differentiation of the labyrinthine syncytiotrophoblasts appeared normal
• at E11.5, approximately 70% of homozygous null embryos displayed successful chorioallantoic fusion but showed vascular deficiency in the chorionic plate, resulting in a relatively pale placenta
• in wild-type embryos, chorioallantoic fusion occurred by E10.5; in ~30% of homozygous null embryos, the allantois failed to fuse with the placenta, resulting in atrophy
• at E11.5, approximately 70% of homozygous null embryos displayed successful chorioallantoic fusion but showed vascular deficiency in the chorionic plate, resulting in a relatively pale placenta

cardiovascular system
• homozygous null embryos displayed loss of vascular integrity in large arteries (e.g. the dorsal aorta and umbilical arteries)
• the endothelial lining, the smooth-muscle cell wall, and the pericytes of the dorsal aorta were disorganized and mixed with endothelial cells
• H&E staining revealed the presence of disorganized vascular cells in the mutant dorsal aorta, which appeared to be significantly dilated, resembling a large aneurysm
• homozygous null embryos displayed a specific defect in vessel bifurcation at the chorioallantoic junction, leading to severe undervascularization in the placental labyrinth
• unlike the wild-type labyrinth, the mutant labyrinth was saturated with maternal blood sinuses and few fetal vessels were detected
• notably, trophoblast nuclei were evident in both wild-type and mutant labyrinth, and differentiation of the labyrinthine syncytiotrophoblasts appeared normal
• gelatinase activity in the mutant hearts is greatly diminished, particularly in the muscular component of the IVS and the valvular leaflets where defects are observed
• gelatinase deficiency may compromise the matrix remodeling process that is crucial for fusion of the IVS and AV cushion tissue
• fusion of the inferior and superior cushion tissue was impaired in mutant embryos, as evidenced by gaps between the 2 endocardial cushions
• however, the epithelial to mesenchyme transition was normal in E9.5 AV cushion explants, and cell proliferation was normal in E11.5 and E12.5 AV cushion explants
• at E12.5, a large number of TUNEL- or activated caspase-3 positive apoptotic cells are detectable in the AV cushion tissue proximal to the atrial septum; apoptosis may be detrimental to atrial septum fusion, leading to the ASD phenotype
• 55% (10/18) mutant embryos show complete AVSD
• embryos showed defects in maturation of the interventricular septum, including the fusion of the muscular component that extends as an outgrowth of the ventricular wall and the membranous component that forms from the AV cushion tissue
• 45% of mutant embryos (8/18) show VSD
• at E14.5, homozygous null embryos were moribund, appeared edematous, and showed evidence of hemorrhage from the umbilical artery, filling the amnion

cellular
• TUNEL analysis revealed the presence of numerous apoptotic vascular cells in homozygous null embryos

Mouse Models of Human Disease
OMIM IDRef(s)
Atrioventricular Septal Defect; AVSD 606215 J:126490


Mouse Genome Informatics
ht2
    Cyr61tm1Lfl/Cyr61+
involves: 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• at E14.5, some mutant mice show dysplastic mitral valves (3/27)
• 20% of adult mutant mice (5/25) show persistent ASD, where the septum primum failed to fuse completely with the cushion tissue and the ostium primum remained
• septum secundum formation was normal, but the postnatal fusion of the two septa was precluded by the defective septum primum; consequently, blood cells were trapped between the atria and the hemodynamic flow was in disarray
• the foramen ovale remained patent in affected adult mice
• at E14.5, some mutant mice show complete AVSD (4/27)
• while a VSD in mutant hearts was apparent at E13.5 and E14.5, it is not seen after E15.5, indicating that interventricular septum formation is delayed in mutant embryos but not persistently impaired
• at E14.5, some mutant mice show VSD (11/27), but this is no longer apparent at E15.5

Mouse Models of Human Disease
OMIM IDRef(s)
Atrial Septal Defect 1; ASD1 108800 J:126490