{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:46:39Z","timestamp":1792507599498,"version":"4.5.0"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"17","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,8,19]]},"abstract":"<jats:p>\n                    Inheritance of an inactivated form of the\n                    <jats:italic>VHL<\/jats:italic>\n                    tumor suppressor gene predisposes patients to develop von Hippel\u2013Lindau disease, and somatic\n                    <jats:italic>VHL<\/jats:italic>\n                    inactivation is an early genetic event leading to the development of sporadic renal cell carcinoma. The\n                    <jats:italic>VHL<\/jats:italic>\n                    gene was disrupted by targeted homologous recombination in murine embryonic stem cells, and a mouse line containing an inactivated\n                    <jats:italic>VHL<\/jats:italic>\n                    allele was generated. While heterozygous\n                    <jats:italic>VHL<\/jats:italic>\n                    (+\/\u2212) mice appeared phenotypically normal,\n                    <jats:italic>VHL<\/jats:italic>\n                    \u2212\/\u2212 mice died\n                    <jats:italic>in utero<\/jats:italic>\n                    at 10.5 to 12.5 days of gestation (E10.5 to E12.5). Homozygous\n                    <jats:italic>VHL<\/jats:italic>\n                    \u2212\/\u2212 embryos appeared to develop normally until E9.5 to E10.5, when placental dysgenesis developed. Embryonic vasculogenesis of the placenta failed to occur in\n                    <jats:italic>VHL<\/jats:italic>\n                    \u2212\/\u2212 mice, and hemorrhagic lesions developed in the placenta. Subsequent hemorrhage in\n                    <jats:italic>VHL<\/jats:italic>\n                    \u2212\/\u2212 embryos caused necrosis and death. These results indicate that VHL expression is critical for normal extraembryonic vascular development.\n                  <\/jats:p>","DOI":"10.1073\/pnas.94.17.9102","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:35:50Z","timestamp":1027679750000},"page":"9102-9107","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":303,"title":["Defective placental vasculogenesis causes embryonic lethality in VHL-deficient\u2009mice"],"prefix":"10.1073","volume":"94","author":[{"given":"James R.","family":"Gnarra","sequence":"first","affiliation":[{"name":"Urologic Oncology Branch, Division of Clinical Sciences, Laboratory of Pathology, and Office of the Director, National Cancer Institute, Bethesda, MD 20892; Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201; and Inheritable Disorders Branch, and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerrold M.","family":"Ward","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch, Division of Clinical Sciences, Laboratory of Pathology, and Office of the Director, National Cancer Institute, Bethesda, MD 20892; Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201; and Inheritable Disorders Branch, and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Forbes D.","family":"Porter","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch, Division of Clinical Sciences, Laboratory of Pathology, and Office of the Director, National Cancer Institute, Bethesda, MD 20892; Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201; and Inheritable Disorders Branch, and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch, Division of Clinical Sciences, Laboratory of Pathology, and Office of the Director, National Cancer Institute, Bethesda, MD 20892; Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201; and Inheritable Disorders Branch, and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah E.","family":"Devor","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch, Division of Clinical Sciences, Laboratory of Pathology, and Office of the Director, National Cancer Institute, Bethesda, MD 20892; Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201; and Inheritable Disorders Branch, and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Grinberg","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch, Division of Clinical Sciences, Laboratory of Pathology, and Office of the Director, National Cancer Institute, Bethesda, MD 20892; Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201; and Inheritable Disorders Branch, and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Emmert-Buck","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch, Division of Clinical Sciences, Laboratory of Pathology, and Office of the Director, National Cancer Institute, Bethesda, MD 20892; Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702-1201; and Inheritable Disorders Branch, and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiner","family":"Westphal","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch, Division of Clinical Sciences, Laboratory of Pathology, and Office of the Director, National Cancer Institute, Bethesda, MD 20892; 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