DEFECTIVE PLACENTAL VASCULOGENESIS CAUSES EMBRYONIC LETHALITY IN VHL-DEFICIENT MICE

Inheritance of an inactivated form of the VHL tumor suppressor gene pr edisposes patients to develop von Hippel-Lindau disease, and somatic V HL inactivation is an early genetic event leading to the development o f sporadic renal cell carcinoma, The VHL gene was disrupted by targete d homologous recombination in murine embryonic stem cells, and a mouse line containing an inactivated VHL allele was generated, While hetero zygous VHL (+/-) mice appeared phenotypically normal, VHL -/- mice die d in utero at 10.5 to 12.5 days of gestation (E10.5 to E12.5). Homozyg ous VHL -/- embryos appeared to develop normally until E9.5 to E10.5, when placental dysgenesis developed, Embryonic vasculogenesis of the p lacenta failed to occur in VHL -/- mice, and hemorrhagic lesions devel oped in the placenta, Subsequent hemorrhage in VHL -/- embryos caused necrosis and death, These results indicate that VHL expression is crit ical for normal extraembryonic vascular development.