Loading…
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...
Saved in:
| Published in: | Proceedings of the National Academy of Sciences - PNAS 1997-08, Vol.94 (17), p.9102-9107 |
|---|---|
| Main Authors: | , , , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| 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!
|
| cited_by | cdi_FETCH-LOGICAL-c584t-25fcdff5ca4acc41913a8c01f602c55c8f3149ed85ce33e1e96adc81fc45000a3 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c584t-25fcdff5ca4acc41913a8c01f602c55c8f3149ed85ce33e1e96adc81fc45000a3 |
| container_end_page | 9107 |
| container_issue | 17 |
| container_start_page | 9102 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 94 |
| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1073/pnas.94.17.9102 |
| format | article |
| fullrecord | <record><control><sourceid>jstor_proqu</sourceid><recordid>TN_cdi_jstor_primary_42564</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>42564</jstor_id><sourcerecordid>42564</sourcerecordid><originalsourceid>FETCH-LOGICAL-c584t-25fcdff5ca4acc41913a8c01f602c55c8f3149ed85ce33e1e96adc81fc45000a3</originalsourceid><addsrcrecordid>eNqFkc1vEzEQxS0EKqFwRkICrTjAadPx164tcUGhUKQgkIBeLdcZt46cdbrerch_j1eJosIBTj6833uemUfIcwpzCi0_23Y2z7WY03auKbAHZEZB07oRGh6SGQBrayWYeEye5LwGAC0VnJATzWQjBJuR7x_QoxvCHVbfonXYDTZWlza7MaZr7DCHXC3smDFX55urfpe64KolDjc2hmFXha66vFjWJSS4UMzVl-DwKXnkbcz47PCekp8fz38sLurl10-fF--XtZNKDDWT3q28l84K65ygmnKrHFDfAHNSOuU5FRpXSjrkHCnqxq6cot4JWTax_JS82-dux6sNrqbhexvNtg8b2-9MssH8qXThxlynO8M4SF7sbw72Pt2OmAezCdlhjLbDNGbTagZK8f-DtIG2aYAW8PVf4DqNfVduYFiRgalWFuhsD7k-5dyjPw5MwUydmqlTo4WhrZk6LY6X9_c88ocSi_7qoE_Go3o_4O0_AePHGAf8NRTyxZ5c5yH1R1RMP_Hfsoi_Ow</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>201302875</pqid></control><display><type>article</type><title>Defective Placental Vasculogenesis Causes Embryonic Lethality in VHL-Deficient Mice</title><source>JSTOR Archival Journals and Primary Sources Collection</source><source>PubMed Central</source><creator>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</creator><creatorcontrib>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</creatorcontrib><description>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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.94.17.9102</identifier><identifier>PMID: 9256442</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1997-08, Vol.94 (17), p.9102-9107</ispartof><rights>Copyright 1997 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Aug 19, 1997</rights><rights>1997</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c584t-25fcdff5ca4acc41913a8c01f602c55c8f3149ed85ce33e1e96adc81fc45000a3</citedby><cites>FETCH-LOGICAL-c584t-25fcdff5ca4acc41913a8c01f602c55c8f3149ed85ce33e1e96adc81fc45000a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/94/17.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/42564$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/42564$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792,58237,58470</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9256442$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gnarra, James R.</creatorcontrib><creatorcontrib>Ward, Jerrold M.</creatorcontrib><creatorcontrib>Porter, Forbes D.</creatorcontrib><creatorcontrib>Wagner, Joseph R.</creatorcontrib><creatorcontrib>Devor, Deborah E.</creatorcontrib><creatorcontrib>Grinberg, Alex</creatorcontrib><creatorcontrib>Emmert-Buck, Michael R.</creatorcontrib><creatorcontrib>Westphal, Heiner</creatorcontrib><creatorcontrib>Klausner, Richard D.</creatorcontrib><creatorcontrib>Linehan, W. Marston</creatorcontrib><title>Defective Placental Vasculogenesis Causes Embryonic Lethality in VHL-Deficient Mice</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Alleles</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Cell lines</subject><subject>Cellular biology</subject><subject>Embryonic and Fetal Development - genetics</subject><subject>Embryos</subject><subject>Endothelial cells</subject><subject>Exons</subject><subject>Female</subject><subject>Fetal Death - genetics</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Genes</subject><subject>Genes, Tumor Suppressor</subject><subject>Genetic engineering</subject><subject>Genetic vectors</subject><subject>Labyrinths</subject><subject>Ligases</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Neovascularization, Physiologic - genetics</subject><subject>Placenta</subject><subject>Placenta - blood supply</subject><subject>Pregnancy</subject><subject>Proteins - genetics</subject><subject>Rodents</subject><subject>Trophoblasts</subject><subject>Tumor Suppressor Proteins</subject><subject>Ubiquitin-Protein Ligases</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><recordid>eNqFkc1vEzEQxS0EKqFwRkICrTjAadPx164tcUGhUKQgkIBeLdcZt46cdbrerch_j1eJosIBTj6833uemUfIcwpzCi0_23Y2z7WY03auKbAHZEZB07oRGh6SGQBrayWYeEye5LwGAC0VnJATzWQjBJuR7x_QoxvCHVbfonXYDTZWlza7MaZr7DCHXC3smDFX55urfpe64KolDjc2hmFXha66vFjWJSS4UMzVl-DwKXnkbcz47PCekp8fz38sLurl10-fF--XtZNKDDWT3q28l84K65ygmnKrHFDfAHNSOuU5FRpXSjrkHCnqxq6cot4JWTax_JS82-dux6sNrqbhexvNtg8b2-9MssH8qXThxlynO8M4SF7sbw72Pt2OmAezCdlhjLbDNGbTagZK8f-DtIG2aYAW8PVf4DqNfVduYFiRgalWFuhsD7k-5dyjPw5MwUydmqlTo4WhrZk6LY6X9_c88ocSi_7qoE_Go3o_4O0_AePHGAf8NRTyxZ5c5yH1R1RMP_Hfsoi_Ow</recordid><startdate>19970819</startdate><enddate>19970819</enddate><creator>Gnarra, James R.</creator><creator>Ward, Jerrold M.</creator><creator>Porter, Forbes D.</creator><creator>Wagner, Joseph R.</creator><creator>Devor, Deborah E.</creator><creator>Grinberg, Alex</creator><creator>Emmert-Buck, Michael R.</creator><creator>Westphal, Heiner</creator><creator>Klausner, Richard D.</creator><creator>Linehan, W. Marston</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19970819</creationdate><title>Defective Placental Vasculogenesis Causes Embryonic Lethality in VHL-Deficient Mice</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c584t-25fcdff5ca4acc41913a8c01f602c55c8f3149ed85ce33e1e96adc81fc45000a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Alleles</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>Cell lines</topic><topic>Cellular biology</topic><topic>Embryonic and Fetal Development - genetics</topic><topic>Embryos</topic><topic>Endothelial cells</topic><topic>Exons</topic><topic>Female</topic><topic>Fetal Death - genetics</topic><topic>Gene Expression Regulation, Developmental</topic><topic>Genes</topic><topic>Genes, Tumor Suppressor</topic><topic>Genetic engineering</topic><topic>Genetic vectors</topic><topic>Labyrinths</topic><topic>Ligases</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Neovascularization, Physiologic - genetics</topic><topic>Placenta</topic><topic>Placenta - blood supply</topic><topic>Pregnancy</topic><topic>Proteins - genetics</topic><topic>Rodents</topic><topic>Trophoblasts</topic><topic>Tumor Suppressor Proteins</topic><topic>Ubiquitin-Protein Ligases</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gnarra, James R.</creatorcontrib><creatorcontrib>Ward, Jerrold M.</creatorcontrib><creatorcontrib>Porter, Forbes D.</creatorcontrib><creatorcontrib>Wagner, Joseph R.</creatorcontrib><creatorcontrib>Devor, Deborah E.</creatorcontrib><creatorcontrib>Grinberg, Alex</creatorcontrib><creatorcontrib>Emmert-Buck, Michael R.</creatorcontrib><creatorcontrib>Westphal, Heiner</creatorcontrib><creatorcontrib>Klausner, Richard D.</creatorcontrib><creatorcontrib>Linehan, W. Marston</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gnarra, James R.</au><au>Ward, Jerrold M.</au><au>Porter, Forbes D.</au><au>Wagner, Joseph R.</au><au>Devor, Deborah E.</au><au>Grinberg, Alex</au><au>Emmert-Buck, Michael R.</au><au>Westphal, Heiner</au><au>Klausner, Richard D.</au><au>Linehan, W. Marston</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Defective Placental Vasculogenesis Causes Embryonic Lethality in VHL-Deficient Mice</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1997-08-19</date><risdate>1997</risdate><volume>94</volume><issue>17</issue><spage>9102</spage><epage>9107</epage><pages>9102-9107</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><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.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>9256442</pmid><doi>10.1073/pnas.94.17.9102</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1997-08, Vol.94 (17), p.9102-9107 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_jstor_primary_42564 |
| source | JSTOR Archival Journals and Primary Sources Collection; PubMed Central |
| 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 |
| title | Defective Placental Vasculogenesis Causes Embryonic Lethality in VHL-Deficient Mice |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-11T17%3A26%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Defective%20Placental%20Vasculogenesis%20Causes%20Embryonic%20Lethality%20in%20VHL-Deficient%20Mice&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Gnarra,%20James%20R.&rft.date=1997-08-19&rft.volume=94&rft.issue=17&rft.spage=9102&rft.epage=9107&rft.pages=9102-9107&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.94.17.9102&rft_dat=%3Cjstor_proqu%3E42564%3C/jstor_proqu%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c584t-25fcdff5ca4acc41913a8c01f602c55c8f3149ed85ce33e1e96adc81fc45000a3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=201302875&rft_id=info:pmid/9256442&rft_jstor_id=42564&rfr_iscdi=true |