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Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice
J R Gnarra1, J M Ward, F D Porter
1Urologic Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
Abstract:
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.
Insights
Von Hippel-Lindau (VHL) gene inactivation causes embryonic death due to placental failure. VHL gene expression is critical for placental vascular development and embryonic survival.
Area of Science:
- Genetics
- Developmental Biology
- Oncology
Background:
- Von Hippel-Lindau (VHL) disease is linked to VHL tumor suppressor gene inactivation.
- VHL inactivation is an early event in sporadic renal cell carcinoma development.
Purpose of the Study:
- To investigate the role of the VHL gene in embryonic development using a mouse model.
- To determine the consequences of VHL gene inactivation on embryonic and placental development.
Main Methods:
- Targeted homologous recombination was used to disrupt the VHL gene in murine embryonic stem cells.
- A mouse line with an inactivated VHL allele was generated and analyzed for embryonic and placental phenotypes.
Main Results:
- VHL -/- mice died in utero between embryonic days 10.5 and 12.5.
- VHL -/- embryos exhibited placental dysgenesis, failed embryonic vasculogenesis, and hemorrhagic lesions.
- These placental defects led to embryonic necrosis and death.
Conclusions:
- VHL gene expression is essential for normal extraembryonic vascular development.
- Placental failure due to VHL inactivation is the cause of embryonic lethality in VHL -/- mice.
- This study highlights the critical role of VHL in placental development, impacting embryonic survival.