Phenotypes Associated with This Genotype

Genotype
MGI:3040322

• Allelic Composition: Ccn1^tm1Lfl/Ccn1^tm1Lfl
• Genetic Background: involves: 129S4/SvJae * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

neonatal lethality, complete penetrance ( J:80618 )

• only a few embryonic survivors developed to term and were born alive, but these mice died within 24 hours of birth

embryonic lethality during organogenesis, incomplete penetrance ( J:80618 )

• 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

embryo

abnormal placenta morphology ( J:80618 )

• 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

abnormal placental labyrinth vasculature morphology ( J:80618 )

• 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

abnormal chorionic plate morphology ( J:80618 )

• 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

pale placenta ( J:80618 )

• 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

failure of chorioallantoic fusion ( J:80618 )

• 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

cardiovascular system

abnormal artery morphology ( J:80618 )

• homozygous null embryos displayed loss of vascular integrity in large arteries (e.g. the dorsal aorta and umbilical arteries)

abnormal dorsal aorta morphology ( J:80618 )

• the endothelial lining, the smooth-muscle cell wall, and the pericytes of the dorsal aorta were disorganized and mixed with endothelial cells

dilated dorsal aorta ( J:80618 )

• 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

abnormal placental labyrinth vasculature morphology ( J:80618 )

• 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

abnormal heart development ( J:126490 )

• 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

failure of atrioventricular cushion closure ( J:126490 )

• 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

common atrioventricular valve ( J:126490 )

complete atrioventricular septal defect ( J:126490 )

• 55% (10/18) mutant embryos show complete AVSD

abnormal interventricular septum morphology ( J:126490 )

• 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

ventricular septal defect ( J:126490 )

• 45% of mutant embryos (8/18) show VSD

hemorrhage ( J:80618 )

• at E14.5, homozygous null embryos were moribund, appeared edematous, and showed evidence of hemorrhage from the umbilical artery, filling the amnion

cellular

abnormal apoptosis ( J:80618 )

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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
atrioventricular septal defect		DOID:0050651	OMIM:606215 OMIM:614430 OMIM:614474	J:126490