Defective Placental Vasculogenesis Causes Embryonic Lethality in VHL-Deficient Mice

Inheritance of an inactivated form of the VHL tumor suppressor gene predisposes patients to develop von Hippel-Lindau disease, and somatic VHL inactivation is an early genetic event leading to the development of sporadic renal cell carcinoma. The VHL gene was disrupted by targeted homologous recombi...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-08, Vol.94 (17), p.9102-9107
Main Authors: Gnarra, James R., Ward, Jerrold M., Porter, Forbes D., Wagner, Joseph R., Devor, Deborah E., Grinberg, Alex, Emmert-Buck, Michael R., Westphal, Heiner, Klausner, Richard D., Linehan, W. Marston
Format: Article
Language:English
Subjects:
Alleles
Animals
Biological Sciences
Cell lines
Cellular biology
Embryonic and Fetal Development - genetics
Embryos
Endothelial cells
Exons
Female
Fetal Death - genetics
Gene Expression Regulation, Developmental
Genes
Genes, Tumor Suppressor
Genetic engineering
Genetic vectors
Labyrinths
Ligases
Mice
Mice, Mutant Strains
Neovascularization, Physiologic - genetics
Placenta
Placenta - blood supply
Pregnancy
Proteins - genetics
Rodents
Trophoblasts
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases
Von Hippel-Lindau Tumor Suppressor Protein
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Inheritance of an inactivated form of the VHL tumor suppressor gene predisposes patients to develop von Hippel-Lindau disease, and somatic VHL inactivation is an early genetic event leading to the development of sporadic renal cell carcinoma. The VHL gene was disrupted by targeted homologous recombination in murine embryonic stem cells, and a mouse line containing an inactivated VHL allele was generated. While heterozygous VHL (+/-) mice appeared phenotypically normal, VHL -/- mice died in utero at 10.5 to 12.5 days of gestation (E10.5 to E12.5). Homozygous VHL -/- embryos appeared to develop normally until E9.5 to E10.5, when placental dysgenesis developed. Embryonic vasculogenesis of the placenta failed to occur in VHL -/- mice, and hemorrhagic lesions developed in the placenta. Subsequent hemorrhage in VHL -/- embryos caused necrosis and death. These results indicate that VHL expression is critical for normal extraembryonic vascular development.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.17.9102