Nkx2-5 Pathways and Congenital Heart Disease: Loss of Ventricular Myocyte Lineage Specification Leads to Progressive Cardiomyopathy and Complete Heart Block
Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecu...
Gespeichert in:
| Veröffentlicht in: | Cell 2004-04, Vol.117 (3), p.373-386 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 386 |
|---|---|
| container_issue | 3 |
| container_start_page | 373 |
| container_title | Cell |
| container_volume | 117 |
| creator | Pashmforoush, Mohammad Lu, Jonathan T Chen, Hanying Amand, Tara St Kondo, Richard Pradervand, Sylvain Evans, Sylvia M Clark, Bob Feramisco, James R Giles, Wayne Ho, Siew Yen Benson, D.Woodrow Silberbach, Michael Shou, Weinian Chien, Kenneth R |
| description | Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease. |
| doi_str_mv | 10.1016/S0092-8674(04)00405-2 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_71867314</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0092867404004052</els_id><sourcerecordid>71867314</sourcerecordid><originalsourceid>FETCH-LOGICAL-c232t-68e781596d37b2b707231661b67f870ac9c3606df7d407a2c5309a23e7352bb93</originalsourceid><addsrcrecordid>eNo9kcFu1DAQhi0EotvCI4B8QvQQGNtJnHCpYIEWKUClAlfLsSeLaRIH29uSd-Fhm-0uSCPN5dP_j-Yj5BmDVwxY-foKoOZZVcr8JeSnADkUGX9AVgxqmeVM8odk9R85Iscx_gKAqiiKx-SIFQuW13JF_n65_sOzgl7q9PNWz5Hq0dK1Hzc4uqR7eoE6JPreRdQR39DGx0h9R3_gmIIz214H-nn2Zk5IGzei3iC9mtC4zhmdnB9pg9pGmjy9DH4TMEZ3g3Stg3V-mP201M6HzmHqcYnZN77rvbl-Qh51uo_49LBPyPePH76tL7Lm6_mn9dsmM1zwlJUVyooVdWmFbHkrQXLBypK1pewqCdrURpRQ2k7aHKTmphBQay5QioK3bS1OyIt97hT87y3GpAYXDfa9HtFvo5JseaJg-QI-P4DbdkCrpuAGHWb1758LcLYHcDn3xmFQ0TgcDVoX0CRlvVMM1M6gujeodnoULLMzqLi4A_NhjXA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>71867314</pqid></control><display><type>article</type><title>Nkx2-5 Pathways and Congenital Heart Disease: Loss of Ventricular Myocyte Lineage Specification Leads to Progressive Cardiomyopathy and Complete Heart Block</title><source>MEDLINE</source><source>Cell Press Free Archives</source><source>Access via ScienceDirect (Elsevier)</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Pashmforoush, Mohammad ; Lu, Jonathan T ; Chen, Hanying ; Amand, Tara St ; Kondo, Richard ; Pradervand, Sylvain ; Evans, Sylvia M ; Clark, Bob ; Feramisco, James R ; Giles, Wayne ; Ho, Siew Yen ; Benson, D.Woodrow ; Silberbach, Michael ; Shou, Weinian ; Chien, Kenneth R</creator><creatorcontrib>Pashmforoush, Mohammad ; Lu, Jonathan T ; Chen, Hanying ; Amand, Tara St ; Kondo, Richard ; Pradervand, Sylvain ; Evans, Sylvia M ; Clark, Bob ; Feramisco, James R ; Giles, Wayne ; Ho, Siew Yen ; Benson, D.Woodrow ; Silberbach, Michael ; Shou, Weinian ; Chien, Kenneth R</creatorcontrib><description>Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/S0092-8674(04)00405-2</identifier><identifier>PMID: 15109497</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acetylcholinesterase - metabolism ; Aging ; Animals ; Animals, Newborn ; Cardiomyopathies - genetics ; Cardiomyopathies - pathology ; Cell Lineage ; Electric Conductivity ; Electrocardiography ; Gene Deletion ; Gene Expression ; Gene Expression Profiling ; Gene Targeting ; Genes, Reporter ; Heart Block - embryology ; Heart Block - genetics ; Heart Block - physiopathology ; Heart Defects, Congenital - complications ; Heart Defects, Congenital - physiopathology ; Heart Ventricles - cytology ; Homeobox Protein Nkx-2.5 ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Mice ; Mice, Knockout ; Myocytes, Cardiac - cytology ; Reproducibility of Results ; Time Factors ; Transcription Factors - deficiency ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcription, Genetic</subject><ispartof>Cell, 2004-04, Vol.117 (3), p.373-386</ispartof><rights>2004 Cell Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c232t-68e781596d37b2b707231661b67f870ac9c3606df7d407a2c5309a23e7352bb93</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0092-8674(04)00405-2$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>315,782,786,3554,27933,27934,46004</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15109497$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pashmforoush, Mohammad</creatorcontrib><creatorcontrib>Lu, Jonathan T</creatorcontrib><creatorcontrib>Chen, Hanying</creatorcontrib><creatorcontrib>Amand, Tara St</creatorcontrib><creatorcontrib>Kondo, Richard</creatorcontrib><creatorcontrib>Pradervand, Sylvain</creatorcontrib><creatorcontrib>Evans, Sylvia M</creatorcontrib><creatorcontrib>Clark, Bob</creatorcontrib><creatorcontrib>Feramisco, James R</creatorcontrib><creatorcontrib>Giles, Wayne</creatorcontrib><creatorcontrib>Ho, Siew Yen</creatorcontrib><creatorcontrib>Benson, D.Woodrow</creatorcontrib><creatorcontrib>Silberbach, Michael</creatorcontrib><creatorcontrib>Shou, Weinian</creatorcontrib><creatorcontrib>Chien, Kenneth R</creatorcontrib><title>Nkx2-5 Pathways and Congenital Heart Disease: Loss of Ventricular Myocyte Lineage Specification Leads to Progressive Cardiomyopathy and Complete Heart Block</title><title>Cell</title><addtitle>Cell</addtitle><description>Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.</description><subject>Acetylcholinesterase - metabolism</subject><subject>Aging</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Cardiomyopathies - genetics</subject><subject>Cardiomyopathies - pathology</subject><subject>Cell Lineage</subject><subject>Electric Conductivity</subject><subject>Electrocardiography</subject><subject>Gene Deletion</subject><subject>Gene Expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Targeting</subject><subject>Genes, Reporter</subject><subject>Heart Block - embryology</subject><subject>Heart Block - genetics</subject><subject>Heart Block - physiopathology</subject><subject>Heart Defects, Congenital - complications</subject><subject>Heart Defects, Congenital - physiopathology</subject><subject>Heart Ventricles - cytology</subject><subject>Homeobox Protein Nkx-2.5</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Reproducibility of Results</subject><subject>Time Factors</subject><subject>Transcription Factors - deficiency</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kcFu1DAQhi0EotvCI4B8QvQQGNtJnHCpYIEWKUClAlfLsSeLaRIH29uSd-Fhm-0uSCPN5dP_j-Yj5BmDVwxY-foKoOZZVcr8JeSnADkUGX9AVgxqmeVM8odk9R85Iscx_gKAqiiKx-SIFQuW13JF_n65_sOzgl7q9PNWz5Hq0dK1Hzc4uqR7eoE6JPreRdQR39DGx0h9R3_gmIIz214H-nn2Zk5IGzei3iC9mtC4zhmdnB9pg9pGmjy9DH4TMEZ3g3Stg3V-mP201M6HzmHqcYnZN77rvbl-Qh51uo_49LBPyPePH76tL7Lm6_mn9dsmM1zwlJUVyooVdWmFbHkrQXLBypK1pewqCdrURpRQ2k7aHKTmphBQay5QioK3bS1OyIt97hT87y3GpAYXDfa9HtFvo5JseaJg-QI-P4DbdkCrpuAGHWb1758LcLYHcDn3xmFQ0TgcDVoX0CRlvVMM1M6gujeodnoULLMzqLi4A_NhjXA</recordid><startdate>20040430</startdate><enddate>20040430</enddate><creator>Pashmforoush, Mohammad</creator><creator>Lu, Jonathan T</creator><creator>Chen, Hanying</creator><creator>Amand, Tara St</creator><creator>Kondo, Richard</creator><creator>Pradervand, Sylvain</creator><creator>Evans, Sylvia M</creator><creator>Clark, Bob</creator><creator>Feramisco, James R</creator><creator>Giles, Wayne</creator><creator>Ho, Siew Yen</creator><creator>Benson, D.Woodrow</creator><creator>Silberbach, Michael</creator><creator>Shou, Weinian</creator><creator>Chien, Kenneth R</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20040430</creationdate><title>Nkx2-5 Pathways and Congenital Heart Disease: Loss of Ventricular Myocyte Lineage Specification Leads to Progressive Cardiomyopathy and Complete Heart Block</title><author>Pashmforoush, Mohammad ; Lu, Jonathan T ; Chen, Hanying ; Amand, Tara St ; Kondo, Richard ; Pradervand, Sylvain ; Evans, Sylvia M ; Clark, Bob ; Feramisco, James R ; Giles, Wayne ; Ho, Siew Yen ; Benson, D.Woodrow ; Silberbach, Michael ; Shou, Weinian ; Chien, Kenneth R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c232t-68e781596d37b2b707231661b67f870ac9c3606df7d407a2c5309a23e7352bb93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Acetylcholinesterase - metabolism</topic><topic>Aging</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Cardiomyopathies - genetics</topic><topic>Cardiomyopathies - pathology</topic><topic>Cell Lineage</topic><topic>Electric Conductivity</topic><topic>Electrocardiography</topic><topic>Gene Deletion</topic><topic>Gene Expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Targeting</topic><topic>Genes, Reporter</topic><topic>Heart Block - embryology</topic><topic>Heart Block - genetics</topic><topic>Heart Block - physiopathology</topic><topic>Heart Defects, Congenital - complications</topic><topic>Heart Defects, Congenital - physiopathology</topic><topic>Heart Ventricles - cytology</topic><topic>Homeobox Protein Nkx-2.5</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Myocytes, Cardiac - cytology</topic><topic>Reproducibility of Results</topic><topic>Time Factors</topic><topic>Transcription Factors - deficiency</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pashmforoush, Mohammad</creatorcontrib><creatorcontrib>Lu, Jonathan T</creatorcontrib><creatorcontrib>Chen, Hanying</creatorcontrib><creatorcontrib>Amand, Tara St</creatorcontrib><creatorcontrib>Kondo, Richard</creatorcontrib><creatorcontrib>Pradervand, Sylvain</creatorcontrib><creatorcontrib>Evans, Sylvia M</creatorcontrib><creatorcontrib>Clark, Bob</creatorcontrib><creatorcontrib>Feramisco, James R</creatorcontrib><creatorcontrib>Giles, Wayne</creatorcontrib><creatorcontrib>Ho, Siew Yen</creatorcontrib><creatorcontrib>Benson, D.Woodrow</creatorcontrib><creatorcontrib>Silberbach, Michael</creatorcontrib><creatorcontrib>Shou, Weinian</creatorcontrib><creatorcontrib>Chien, Kenneth R</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pashmforoush, Mohammad</au><au>Lu, Jonathan T</au><au>Chen, Hanying</au><au>Amand, Tara St</au><au>Kondo, Richard</au><au>Pradervand, Sylvain</au><au>Evans, Sylvia M</au><au>Clark, Bob</au><au>Feramisco, James R</au><au>Giles, Wayne</au><au>Ho, Siew Yen</au><au>Benson, D.Woodrow</au><au>Silberbach, Michael</au><au>Shou, Weinian</au><au>Chien, Kenneth R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nkx2-5 Pathways and Congenital Heart Disease: Loss of Ventricular Myocyte Lineage Specification Leads to Progressive Cardiomyopathy and Complete Heart Block</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2004-04-30</date><risdate>2004</risdate><volume>117</volume><issue>3</issue><spage>373</spage><epage>386</epage><pages>373-386</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15109497</pmid><doi>10.1016/S0092-8674(04)00405-2</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0092-8674 |
| ispartof | Cell, 2004-04, Vol.117 (3), p.373-386 |
| issn | 0092-8674 1097-4172 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_71867314 |
| source | MEDLINE; Cell Press Free Archives; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals |
| subjects | Acetylcholinesterase - metabolism Aging Animals Animals, Newborn Cardiomyopathies - genetics Cardiomyopathies - pathology Cell Lineage Electric Conductivity Electrocardiography Gene Deletion Gene Expression Gene Expression Profiling Gene Targeting Genes, Reporter Heart Block - embryology Heart Block - genetics Heart Block - physiopathology Heart Defects, Congenital - complications Heart Defects, Congenital - physiopathology Heart Ventricles - cytology Homeobox Protein Nkx-2.5 Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Mice Mice, Knockout Myocytes, Cardiac - cytology Reproducibility of Results Time Factors Transcription Factors - deficiency Transcription Factors - genetics Transcription Factors - metabolism Transcription, Genetic |
| title | Nkx2-5 Pathways and Congenital Heart Disease: Loss of Ventricular Myocyte Lineage Specification Leads to Progressive Cardiomyopathy and Complete Heart Block |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-02T13%3A48%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Nkx2-5%20Pathways%20and%20Congenital%20Heart%20Disease:%20Loss%20of%20Ventricular%20Myocyte%20Lineage%20Specification%20Leads%20to%20Progressive%20Cardiomyopathy%20and%20Complete%20Heart%20Block&rft.jtitle=Cell&rft.au=Pashmforoush,%20Mohammad&rft.date=2004-04-30&rft.volume=117&rft.issue=3&rft.spage=373&rft.epage=386&rft.pages=373-386&rft.issn=0092-8674&rft.eissn=1097-4172&rft_id=info:doi/10.1016/S0092-8674(04)00405-2&rft_dat=%3Cproquest_pubme%3E71867314%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=71867314&rft_id=info:pmid/15109497&rft_els_id=S0092867404004052&rfr_iscdi=true |