PMID:20460370

Citation	Mandel, EM, Kaltenbrun, E, Callis, TE, Zeng, XX, Marques, SR, Yelon, D, Wang, DZ and Conlon, FL (2010) The BMP pathway acts to directly regulate Tbx20 in the developing heart. Development 137:1919-29
Abstract	TBX20 has been shown to be essential for vertebrate heart development. Mutations within the TBX20 coding region are associated with human congenital heart disease, and the loss of Tbx20 in a wide variety of model systems leads to cardiac defects and eventually heart failure. Despite the crucial role of TBX20 in a range of cardiac cellular processes, the signal transduction pathways that act upstream of Tbx20 remain unknown. Here, we have identified and characterized a conserved 334 bp Tbx20 cardiac regulatory element that is directly activated by the BMP/SMAD1 signaling pathway. We demonstrate that this element is both necessary and sufficient to drive cardiac-specific expression of Tbx20 in Xenopus, and that blocking SMAD1 signaling in vivo specifically abolishes transcription of Tbx20, but not that of other cardiac factors, such as Tbx5 and MHC, in the developing heart. We further demonstrate that activation of Tbx20 by SMAD1 is mediated by a set of novel, non-canonical, high-affinity SMAD-binding sites located within this regulatory element and that phospho-SMAD1 directly binds a non-canonical SMAD1 site in vivo. Finally, we show that these non-canonical sites are necessary and sufficient for Tbx20 expression in Xenopus, and that reporter constructs containing these sites are expressed in a cardiac-specific manner in zebrafish and mouse. Collectively, our findings define Tbx20 as a direct transcriptional target of the BMP/SMAD1 signaling pathway during cardiac maturation.
Links	PubMed PMC2867324 Online version:10.1242/dev.043588
Keywords	Animals; Animals, Genetically Modified; Base Sequence; Binding Sites; Bone Morphogenetic Proteins/genetics; Bone Morphogenetic Proteins/metabolism; DNA Primers/genetics; Gene Expression Regulation, Developmental; Genes, Reporter; Heart/embryology; Humans; Mice; Myocardium/metabolism; Signal Transduction; Smad Proteins/genetics; Smad Proteins/metabolism; T-Box Domain Proteins/genetics; T-Box Domain Proteins/metabolism; Xenopus/embryology; Xenopus/genetics; Xenopus/metabolism; Xenopus laevis/embryology; Xenopus laevis/genetics; Xenopus laevis/metabolism; Zebrafish/embryology; Zebrafish/genetics; Zebrafish/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
XENLA:TBX20	involved_in	GO:0007507: heart development	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
XENLA:TBX20		GO:0007507: heart development	ECO:0000315:		P		Figure 5, Figure 7 SMAD1 activation is required for the expression of Tbx20. Tbx20 serves as a direct transcriptional target of theBMP/SMAD1 signaling pathway and is essential for cardiac development.	complete CACAO 2855

References

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