Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration
Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte f...
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Veröffentlicht in: | Development (Cambridge) 2014-08, Vol.141 (16), p.3112-3122 |
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creator | Schindler, Yocheved L Garske, Kristina M Wang, Jinhu Firulli, Beth A Firulli, Anthony B Poss, Kenneth D Yelon, Deborah |
description | Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine. |
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The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine.</description><identifier>ISSN: 0950-1991</identifier><identifier>EISSN: 1477-9129</identifier><identifier>DOI: 10.1242/dev.106336</identifier><identifier>PMID: 25038045</identifier><language>eng</language><publisher>England: The Company of Biologists</publisher><subject>Amino Acid Sequence ; Animals ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Basic Helix-Loop-Helix Transcription Factors - physiology ; Cell Proliferation ; Danio rerio ; DNA - chemistry ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Genotype ; Heart - embryology ; In Situ Hybridization ; In Situ Hybridization, Fluorescence ; Mice ; Molecular Sequence Data ; Myocytes, Cardiac - cytology ; Regeneration ; Sequence Homology, Amino Acid ; Stem Cells and Regeneration ; Transgenes ; Zebrafish - embryology ; Zebrafish Proteins - genetics ; Zebrafish Proteins - physiology</subject><ispartof>Development (Cambridge), 2014-08, Vol.141 (16), p.3112-3122</ispartof><rights>2014. Published by The Company of Biologists Ltd.</rights><rights>2014. Published by The Company of Biologists Ltd 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-3aa474421466e2df8948e2a419acf5dff65b3c9128815b5d19fb084f09d119023</citedby><cites>FETCH-LOGICAL-c477t-3aa474421466e2df8948e2a419acf5dff65b3c9128815b5d19fb084f09d119023</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3678,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25038045$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schindler, Yocheved L</creatorcontrib><creatorcontrib>Garske, Kristina M</creatorcontrib><creatorcontrib>Wang, Jinhu</creatorcontrib><creatorcontrib>Firulli, Beth A</creatorcontrib><creatorcontrib>Firulli, Anthony B</creatorcontrib><creatorcontrib>Poss, Kenneth D</creatorcontrib><creatorcontrib>Yelon, Deborah</creatorcontrib><title>Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration</title><title>Development (Cambridge)</title><addtitle>Development</addtitle><description>Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Transcription Factors - physiology</subject><subject>Cell Proliferation</subject><subject>Danio rerio</subject><subject>DNA - chemistry</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Genotype</subject><subject>Heart - embryology</subject><subject>In Situ Hybridization</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Regeneration</subject><subject>Sequence Homology, Amino Acid</subject><subject>Stem Cells and Regeneration</subject><subject>Transgenes</subject><subject>Zebrafish - embryology</subject><subject>Zebrafish Proteins - genetics</subject><subject>Zebrafish Proteins - physiology</subject><issn>0950-1991</issn><issn>1477-9129</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9v1DAQxS0EokvhwgdAPiKklPG_OL4goQooUiUu7YmD5djj3aAkXuxkpe2nx9WWCk49zWF-8-bNPELeMrhgXPKPAQ8XDFoh2mdkw6TWjWHcPCcbMAoaZgw7I69K-QUAotX6JTnjCkQHUm3Izys3B05xxINbsFDvchjSdEz-uCDd5xRWvwxppmHNw7yld9hnF4eyozt0eaF1N45pP-G80KpEM25xxuzuZ16TF9GNBd881HNy-_XLzeVVc_3j2_fLz9eNr16XRjgntZScybZFHmJnZIfcSWacjyrE2Kpe-HpS1zHVq8BM7KGTEUxgzAAX5-TTSXe_9hMGX71kN9p9HiaXjza5wf7fmYed3aaDrSu0kqIKvH8QyOn3imWx01A8jqObMa3Fsg66VoOQ8DSqFBcaeKsr-uGE-pxKyRgfHTGw98HZ-jx7Cq7C7_694RH9m5T4A3-ClYY</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Schindler, Yocheved L</creator><creator>Garske, Kristina M</creator><creator>Wang, Jinhu</creator><creator>Firulli, Beth A</creator><creator>Firulli, Anthony B</creator><creator>Poss, Kenneth D</creator><creator>Yelon, Deborah</creator><general>The Company of Biologists</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>7X8</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20140801</creationdate><title>Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration</title><author>Schindler, Yocheved L ; Garske, Kristina M ; Wang, Jinhu ; Firulli, Beth A ; Firulli, Anthony B ; Poss, Kenneth D ; Yelon, Deborah</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-3aa474421466e2df8948e2a419acf5dff65b3c9128815b5d19fb084f09d119023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Basic Helix-Loop-Helix Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Transcription Factors - physiology</topic><topic>Cell Proliferation</topic><topic>Danio rerio</topic><topic>DNA - chemistry</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Developmental</topic><topic>Genotype</topic><topic>Heart - embryology</topic><topic>In Situ Hybridization</topic><topic>In Situ Hybridization, Fluorescence</topic><topic>Mice</topic><topic>Molecular Sequence Data</topic><topic>Myocytes, Cardiac - cytology</topic><topic>Regeneration</topic><topic>Sequence Homology, Amino Acid</topic><topic>Stem Cells and Regeneration</topic><topic>Transgenes</topic><topic>Zebrafish - embryology</topic><topic>Zebrafish Proteins - genetics</topic><topic>Zebrafish Proteins - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schindler, Yocheved L</creatorcontrib><creatorcontrib>Garske, Kristina M</creatorcontrib><creatorcontrib>Wang, Jinhu</creatorcontrib><creatorcontrib>Firulli, Beth A</creatorcontrib><creatorcontrib>Firulli, Anthony B</creatorcontrib><creatorcontrib>Poss, Kenneth D</creatorcontrib><creatorcontrib>Yelon, Deborah</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Development (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schindler, Yocheved L</au><au>Garske, Kristina M</au><au>Wang, Jinhu</au><au>Firulli, Beth A</au><au>Firulli, Anthony B</au><au>Poss, Kenneth D</au><au>Yelon, Deborah</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration</atitle><jtitle>Development (Cambridge)</jtitle><addtitle>Development</addtitle><date>2014-08-01</date><risdate>2014</risdate><volume>141</volume><issue>16</issue><spage>3112</spage><epage>3122</epage><pages>3112-3122</pages><issn>0950-1991</issn><eissn>1477-9129</eissn><abstract>Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine.</abstract><cop>England</cop><pub>The Company of Biologists</pub><pmid>25038045</pmid><doi>10.1242/dev.106336</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Amino Acid Sequence Animals Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - physiology Cell Proliferation Danio rerio DNA - chemistry Gene Expression Profiling Gene Expression Regulation, Developmental Genotype Heart - embryology In Situ Hybridization In Situ Hybridization, Fluorescence Mice Molecular Sequence Data Myocytes, Cardiac - cytology Regeneration Sequence Homology, Amino Acid Stem Cells and Regeneration Transgenes Zebrafish - embryology Zebrafish Proteins - genetics Zebrafish Proteins - physiology |
title | Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration |
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