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Article: T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis

TitleT-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis
Authors
Issue Date2005
PublisherThe Company of Biologists Ltd
Citation
Development, 2005, v. 132 n. 10, p. 2475-2487 How to Cite?
AbstractMutations in T-box genes are the cause of several congenital diseases and are implicated in cancer. Tbx20-null mice exhibit severely hypoplastic hearts and express Tbx2, which is normally restricted to outflow tract and atrioventricular canal, throughout the heart. Tbx20 mutant hearts closely resemble those seen in mice overexpressing Tbx2 in myocardium, suggesting that upregulation of Tbx2 can largely account for the cardiac phenotype in Tbx20-null mice. We provide evidence that Tbx2 is a direct target for repression by Tbx20 in developing heart. We have also found that Tbx2 directly binds to the Nmyc1 promoter in developing heart, and can repress expression of the Nmyc1 promoter in transient transfection studies. Repression of Nmyc1 (N-myc) by aberrantly regulated Tbx2 can account in part for the observed cardiac hypoplassia in Tbx20 mutants. Nmyc1 is required for growth and development of multiple organs, including the heart, and overexpression of Nmyc1 is associated with childhood tumors. Despite its clinical relevance, the factors that regulate Nmyc1 expression during development are unknown. Our data present a paradigm by which T-box proteins regulate regional differences in Nmyc1 expression and proliferation to effect organ morphogenesis. We present a model whereby Tbx2 directly represses Nmyc1 in outflow tract and atrioventricular canal of the developing heart, resulting in relatively low proliferation. In chamber myocardium, Tbx20 represses Tbx2, preventing repression of Nmyc1 and resulting in relatively high proliferation. In addition to its role in regulating regional proliferation, we have found that Tbx20 regulates expression of a number of genes that specify regional identity within the heart, thereby coordinating these two important aspects of organ development.
Persistent Identifierhttp://hdl.handle.net/10722/141715
ISSN
2015 Impact Factor: 6.059
2015 SCImago Journal Rankings: 5.239
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCai, CLen_HK
dc.contributor.authorZhou, Wen_HK
dc.contributor.authorYang, Len_HK
dc.contributor.authorBu, Len_HK
dc.contributor.authorQyang, Yen_HK
dc.contributor.authorZhang, Xen_HK
dc.contributor.authorLi, Xen_HK
dc.contributor.authorRosenfeld, MGen_HK
dc.contributor.authorChen, Jen_HK
dc.contributor.authorEvans, Sen_HK
dc.date.accessioned2011-09-27T02:58:47Z-
dc.date.available2011-09-27T02:58:47Z-
dc.date.issued2005en_HK
dc.identifier.citationDevelopment, 2005, v. 132 n. 10, p. 2475-2487en_HK
dc.identifier.issn0950-1991en_HK
dc.identifier.urihttp://hdl.handle.net/10722/141715-
dc.description.abstractMutations in T-box genes are the cause of several congenital diseases and are implicated in cancer. Tbx20-null mice exhibit severely hypoplastic hearts and express Tbx2, which is normally restricted to outflow tract and atrioventricular canal, throughout the heart. Tbx20 mutant hearts closely resemble those seen in mice overexpressing Tbx2 in myocardium, suggesting that upregulation of Tbx2 can largely account for the cardiac phenotype in Tbx20-null mice. We provide evidence that Tbx2 is a direct target for repression by Tbx20 in developing heart. We have also found that Tbx2 directly binds to the Nmyc1 promoter in developing heart, and can repress expression of the Nmyc1 promoter in transient transfection studies. Repression of Nmyc1 (N-myc) by aberrantly regulated Tbx2 can account in part for the observed cardiac hypoplassia in Tbx20 mutants. Nmyc1 is required for growth and development of multiple organs, including the heart, and overexpression of Nmyc1 is associated with childhood tumors. Despite its clinical relevance, the factors that regulate Nmyc1 expression during development are unknown. Our data present a paradigm by which T-box proteins regulate regional differences in Nmyc1 expression and proliferation to effect organ morphogenesis. We present a model whereby Tbx2 directly represses Nmyc1 in outflow tract and atrioventricular canal of the developing heart, resulting in relatively low proliferation. In chamber myocardium, Tbx20 represses Tbx2, preventing repression of Nmyc1 and resulting in relatively high proliferation. In addition to its role in regulating regional proliferation, we have found that Tbx20 regulates expression of a number of genes that specify regional identity within the heart, thereby coordinating these two important aspects of organ development.en_HK
dc.languageengen_US
dc.publisherThe Company of Biologists Ltden_US
dc.relation.ispartofDevelopmenten_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshCell Differentiation - genetics - physiologyen_HK
dc.subject.meshCell Proliferationen_HK
dc.subject.meshChromatin Immunoprecipitationen_HK
dc.subject.meshDNA Primersen_HK
dc.subject.meshGene Expression Regulation, Developmentalen_HK
dc.subject.meshGene Targetingen_HK
dc.subject.meshHeart - embryologyen_HK
dc.subject.meshIn Situ Hybridizationen_HK
dc.subject.meshIn Situ Nick-End Labelingen_HK
dc.subject.meshMice - embryology - geneticsen_HK
dc.subject.meshModels, Biologicalen_HK
dc.subject.meshMorphogenesisen_HK
dc.subject.meshMutagenesis, Site-Directeden_HK
dc.subject.meshPromoter Regions, Genetic - geneticsen_HK
dc.subject.meshT-Box Domain Proteins - genetics - metabolismen_HK
dc.titleT-box genes coordinate regional rates of proliferation and regional specification during cardiogenesisen_HK
dc.typeArticleen_HK
dc.identifier.emailBu, L:leibu@hku.hken_HK
dc.identifier.authorityBu, L=rp01534en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1242/dev.01832en_HK
dc.identifier.pmid15843407-
dc.identifier.scopuseid_2-s2.0-21044454606en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-21044454606&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume132en_HK
dc.identifier.issue10en_HK
dc.identifier.spage2475en_HK
dc.identifier.epage2487en_HK
dc.identifier.isiWOS:000229890600020-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridCai, CL=7202874136en_HK
dc.identifier.scopusauthoridZhou, W=8510445100en_HK
dc.identifier.scopusauthoridYang, L=8303959000en_HK
dc.identifier.scopusauthoridBu, L=8510445400en_HK
dc.identifier.scopusauthoridQyang, Y=6506533054en_HK
dc.identifier.scopusauthoridZhang, X=8510445700en_HK
dc.identifier.scopusauthoridLi, X=26642998300en_HK
dc.identifier.scopusauthoridRosenfeld, MG=35356018800en_HK
dc.identifier.scopusauthoridChen, J=7501887040en_HK
dc.identifier.scopusauthoridEvans, S=35583946900en_HK

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