Genetic and Molecular Investigation of Tbx20 in Cardiac Development Project Summary: Cardiogenesis, the induction and subsequent development of the heart, is a critical event during embryogenesis. Mutations of genes expressed in the early heart cause defective cardiac development, and are responsible for embryonic lethality and congenital heart disease (CHD), occurring in ~1% of live births and ~10% of stillbirths in humans. T-box genes encode transcription factors (TFs) that play vital roles for the development of various organs. Mutations in T-box genes (e.g., TBX1, 2, 3, 4, 5, 9 and 22) are associated with human diseases with birth defects. Tbx20 is an ancient T-box family gene with orthologues present in species from Drosophila to human. In mammals, Tbx20 is highly expressed in the developing heart, and cardiac expression is maintained from embryonic stages to adulthood. Given the conserved expression of Tbx20 in cardiac tissues across species, we hypothesize that Tbx20 is a key transcription factor (TF) that extensively contributes to cardiac development and function from early embryonic stage to adulthood in mammals. My previous studies have revealed that disruption of Tbx20 leads to embryonic lethality due to proliferative defects of early chamber myocardium (E9.5-E10.5 in mouse), while the roles of Tbx20 for non- chamber myocardial development are still largely unknown. Our long-term objectives are to study the biology of Tbx20 in order to obtain a comprehensive understanding of how this important TF regulates heart development, and how dysfunction of Tbx20 correlates with human CHD. In this study, we will specifically examine the role of Tbx20 in the development of three key cardiac components- the outflow tract (OFT), atrioventricular canal (AVC), and epicardium. In further, we will decipher the regulatory network of Tbx20 in order to fully understand how this important TF mechanistically effects heart formation and function.

Public Health Relevance

Our study uses mouse as a model system to examine the role of T-box transcription factor Tbx20 in the development of epicardium, outflow tract and atrioventricular canal of the heart. We will also examine regulatory network of Tbx20 in order to fully understand how this gene effects heart formation and function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095810-04
Application #
8440751
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2010-04-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$399,376
Indirect Cost
$163,756
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Yan, Jianyun; Li, Jun; Hu, Jun et al. (2018) Smad4 deficiency impairs chondrocyte hypertrophy via the Runx2 transcription factor in mouse skeletal development. J Biol Chem 293:9162-9175
Yan, Jianyun; Zhang, Lu; Sultana, Nishat et al. (2015) A Murine Myh6MerCreMer Knock-In Allele Specifically Mediates Temporal Genetic Deletion in Cardiomyocytes after Tamoxifen Induction. PLoS One 10:e0133472
Yan, Jianyun; Sultana, Nishat; Zhang, Lu et al. (2015) Generation of a tamoxifen inducible Tnnt2MerCreMer knock-in mouse model for cardiac studies. Genesis 53:377-86
Wang, Jiapeng; Li, Zhaomin; He, Yongzheng et al. (2014) Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice. Blood 123:541-53
Yan, Jianyun; Zhang, Lu; Xu, Jinshu et al. (2014) Smad4 regulates ureteral smooth muscle cell differentiation during mouse embryogenesis. PLoS One 9:e104503
Zhang, Lu; Nomura-Kitabayashi, Aya; Sultana, Nishat et al. (2014) Mesodermal Nkx2.5 is necessary and sufficient for early second heart field development. Dev Biol 390:68-79
Wu, Meng; Peng, Siwu; Yang, Jialiang et al. (2014) Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node. Cell Res 24:1201-13
Cai, Xiaoqiang; Zhang, Weijia; Hu, Jun et al. (2013) Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis. Development 140:3176-87
Grisanti, Laura; Clavel, Carlos; Cai, Xiaoqiang et al. (2013) Tbx18 targets dermal condensates for labeling, isolation, and gene ablation during embryonic hair follicle formation. J Invest Dermatol 133:344-53
Cai, Xiaoqiang; Nomura-Kitabayashi, Aya; Cai, Weibin et al. (2011) Myocardial Tbx20 regulates early atrioventricular canal formation and endocardial epithelial-mesenchymal transition via Bmp2. Dev Biol 360:381-90