cardiovascular system phenotype

• abnormal angiogenesis
  • homozygous null embryos displayed defective angiogenesis of the yolk sac and branchial arches
  (MGI Ref ID J:39730)

• absent vitelline blood vessels
  • other mutant yolk sacs lacked large vitelline blood vessels and had enlarged capillaries instead
  (MGI Ref ID J:39730)

• disorganized yolk sac vascular plexus
  • in some mutant yolk sacs, there were fewer capillaries and these appeared to be fused with one another generating an abnormal vascular plexus
  (MGI Ref ID J:39730)

embryo phenotype

• embryonic growth retardation
  • notably, individual organ systems appeared morphologically normal relative to wild-type
  (MGI Ref ID J:39730)
  • at E9.5, mutant embryos appeared developmentally stunted
  (MGI Ref ID J:39730)

• abnormal spongiotrophoblast layer morphology
  • at E8.5, mutant placentas showed normal numbers of spongiotrophoblast cells that disappeared by E9.5 with no increase in TUNEL+ apoptotic cells, suggesting that spongiotrophoblasts themselves differentiated into giant cells at increased rates
  (MGI Ref ID J:66515)
  • at E9.5, mutant placentas showed a severe reduction in diploid spongiotrophoblast cell numbers and a significant expansion in the giant cell population
  (MGI Ref ID J:66515)

• absent vitelline blood vessels
  • other mutant yolk sacs lacked large vitelline blood vessels and had enlarged capillaries instead
  (MGI Ref ID J:39730)

• absent placental labyrinth
  • complete loss of the labyrinthine layer resulted in decreased exchange between maternal and fetal circulations and subsequent intrauterine growth retardation
  (MGI Ref ID J:66515)

• abnormal placenta development
  • mutant placentas contained no fetal vessels and were significantly smaller relative to wild-type
  (MGI Ref ID J:66515)

• abnormal chorionic plate morphology
  • although mutant endothelial cells entered the allantois and chorioallantoic fusion took place, mutant fetal blood vessels failed to invade the chorionic plate by E9.5
  (MGI Ref ID J:66515)

• abnormal trophoblast giant cell morphology
  • in contrast to wild-type, homozygous null trophoblast stem (TS) cells cultured under low oxygen tension failed to generate spongiotrophoblasts in vitro
  (MGI Ref ID J:66515)
  • at E8.5, mutant placentas showed normal numbers of spongiotrophoblast cells that disappeared by E9.5 with no increase in TUNEL+ apoptotic cells, suggesting that spongiotrophoblasts themselves differentiated into giant cells at increased rates
  (MGI Ref ID J:66515)
  • at E9.5, mutant placentas showed a severe reduction in diploid spongiotrophoblast cell numbers and a significant expansion in the giant cell population
  (MGI Ref ID J:66515)

• abnormal visceral yolk sac morphology
  • at E9.5, many mutant yolk sacs contained normal blood islands but lacked normal vasculature
  (MGI Ref ID J:39730)
  • mutant yolk sacs contained a reduced number of surrounding smooth muscle cells in vitelline vessels
  (MGI Ref ID J:39730)

• disorganized yolk sac vascular plexus
  • in some mutant yolk sacs, there were fewer capillaries and these appeared to be fused with one another generating an abnormal vascular plexus
  (MGI Ref ID J:39730)

• abnormal trophoblast layer morphology
  • mutant placentas showed poor trophoblast invasion of maternal myometrium, similar to preeclamptic human placentas
  (MGI Ref ID J:66515)

• decreased embryo size
  • at E9.5, mutant embryos appeared smaller and generally wasted
  (MGI Ref ID J:39730)

growth/size/body region phenotype

• embryonic growth retardation
  • notably, individual organ systems appeared morphologically normal relative to wild-type
  (MGI Ref ID J:39730)
  • at E9.5, mutant embryos appeared developmentally stunted
  (MGI Ref ID J:39730)

• decreased embryo size
  • at E9.5, mutant embryos appeared smaller and generally wasted
  (MGI Ref ID J:39730)

hematopoietic system phenotype

• impaired hematopoiesis
  • this defect appeared to be cell extrinsic as homozygous null ES cells contributed competitively to all hematopoietic lineages in chimeric mice; also, the defect was associated with a reduction in ARNT-dependent VEGFA expression, and was reversed by exogenous VEGFA
  (MGI Ref ID J:70037)
  • ous VEGFA
  (MGI Ref ID J:70037)
  • as early as E8.5, mutant embryos showed a significant decrease in the number of yolk sac hematopoietic progenitors
  (MGI Ref ID J:70037)

mammalian phenotype

• cellular phenotype
  • Normal - mutant ES cells failed to activate genes that normally respond to low oxygen tension (hypoxia)
  (MGI Ref ID J:39730)
  • Normal - aggregation of mutant ES cells with tetraploid wild-type embryos rescued their placental defects; however, these embryos still died from yolk sac vascular and cardiac defects (reduced endocardial cushions, a hypoplastic ventricular myocardium, an enlarged atrioventricular canal, and distended dorsal aortae)
  (MGI Ref ID J:66515)
  • Normal - atrioventricular canal, and distended dorsal aortae)
  (MGI Ref ID J:66515)
  • Normal - mutant ES cells failed to respond to a decrease in glucose concentration (hypoglycemia)
  (MGI Ref ID J:39730)

• cardiovascular system phenotype
  • Normal - although extraembryonic vascularization was defective, the mutant heart, dorsal aorta and intersomitic vessels appeared normal
  (MGI Ref ID J:39730)

mortality/aging

• embryonic lethality, complete penetrance
  • homozygous null embryos died by E10.5
  (MGI Ref ID J:39730)