Molecular mechanisms of Tbx20 regulation Public Deposited

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  • March 21, 2019
Creator
  • Mandel, Elizabeth Marie
    • Affiliation: College of Arts and Sciences, Department of Biology
Abstract
  • The proper formation of the vertebrate heart involves the orchestration of many complex processes including induction, commitment, cell migration and morphogenesis. Each of these events is controlled by regulated gene expression within multiple transcriptional regulatory networks in a spatially and temporally restricted manner, and only slight changes in gene expression can lead to severe cardiac anomalies. One key example is provided by the T-box transcription factor, TBX20. Homologs of Tbx20 have been described in a variety of organisms including mouse, zebrafish, chick, Xenopus and human, and with Nkx2.5 and Tbx5, it is one of the earliest markers of cardiac tissue. Analyses of TBX20 knockdown in mouse and Xenopus have also demonstrated a requirement for TBX20 in early heart development through an involvement in morphogenesis, cell proliferation and transcriptional regulation. However, the mechanisms controlling the tissue-specific regulation of Tbx20 have yet to be described. Recently, both missense and nonsense mutations within the DNA-binding domain of human TBX20 have been shown to result in diverse cardiac pathologies including septal defects, valve defects, and cardiomyopathy. In an effort to clearly define the origins of such congenital heart defects, it will therefore be necessary to fully understand the transcriptional regulation and localized expression of genes such as Tbx20, that are involved in the earliest stages of cardiac development. To this end, the work described here focuses on the characterization of Tbx20 transcriptional regulation in the developing heart. We first demonstrate that the sequence and expression patterns of multiple T-box genes, including Tbx20, are conserved across species, including in the diploid frog Xenopus tropicalis (X. tropicalis). Our studies next go on to show that Tbx20, unlike other cardiac genes described to date, is expressed throughout all regions of the developing heart including both myocardial and endocardial layers. Utilizing transgenesis in both Xenopus and zebrafish, we have identified and characterized a conserved 334bp regulatory element that is sufficient to drive expression of Tbx20 throughout these regions of the heart. To compliment these studies, we have also demonstrated a role for the BMP signaling pathway in the regulation of Tbx20, whereby the downstream BMP mediator SMAD1 directly binds regions within the cardiac regulatory element to drive gene expression in a dose-dependent fashion. This is the first evidence for a role of specific signaling pathways in the regulation of Tbx20 expression, and provides key insights into the transcriptional regulatory network that is responsible for proper cardiac development.
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  • In Copyright
Advisor
  • Conlon, Frank
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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