Understanding cardiac progenitor pathways is relevant for both congenital and adult heart disease. The LIM homeodomain transcription factor Islet (Isl1) plays a pivotal role in cardiac progenitors during development, and is also expressed in postnatal cardiac progenitors found in rodent and human heart. During cardiogenesis, Isl1 is required for proliferation, survival, and migration of second heart field progenitors, and is expressed both within cardiogenic mesoderm and pharyngeal endoderm. It is not known whether Isl1 is required within mesoderm or endoderm for early heart development. Although isl1 is downregulated in the great majority of progenitors as they enter the heart, recent studies have demonstrated persistent Isl1 expression in distinct subdomains within the heart, including myocardial lineages of the outflow tract and sinoatrial node. Persistence of Isl1 in selected differentiated myocardial lineages suggests later requirements for Isl1 which have not been explored. The hypothesis to be tested in this proposal is that Isl1 is required in endoderm, cardiogenic mesoderm, and in subdomains of differentiated cardiomyocytes for specific aspects of heart development and function, and that defining direct or indirect targets of Isl1 will give mechanistic insights into Isl1 action during cardiogenesis.
The Specific Aims of this proposal are: (1) To determine tissue specific requirements for Isl1 in mesodermal progenitors or pharyngeal endoderm, utilizing Mesp1-cre or Foxa2- inducible cre, and a floxed allele of isl1;(2) To investigate a potential role for Isl1 in differentiated myocardial lineages by ablation of isl1 in differentiated myocardial lineages utilizing an anterior heart field specific-cre (MEF2c-cre) or a conduction system specific-inducible cre (HCN4-CreERT2), and a floxed allele of isl1;and (3) To gain insight into mechanisms by which Isl1 controls cell behaviors, by identifying direct and indirect downstream targets of Isl1 during early cardiogenesis. Results of these studies will give mechanistic insight into pathways by which Isl1 controls cell behaviors and morphogenesis during heart development.

Public Health Relevance

Isl1 is a transcription factor which marks undifferentiated cardiac progenitors and is required for their proliferation, differentiation and migration. Isl1 is also expressed in pharyngeal endoderm, which is adjacent to cardiogenic mesoderm and acts as an inducer. The proposed studies will provide mechanistic insight as to where, when, and how Isl1 is required to effect cell behaviors during cardiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074066-07
Application #
7795006
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2003-07-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$445,449
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Boogerd, Cornelis J; Aneas, Ivy; Sakabe, Noboru et al. (2016) Probing chromatin landscape reveals roles of endocardial TBX20 in septation. J Clin Invest 126:3023-35
Bolt, C Chase; Negi, Soumya; GuimarĂ£es-Camboa, Nuno et al. (2016) Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate. PLoS One 11:e0154413
Liang, Xingqun; Zhang, Qingquan; Cattaneo, Paola et al. (2015) Transcription factor ISL1 is essential for pacemaker development and function. J Clin Invest 125:3256-68
Liang, Xingqun; Wang, Gang; Lin, Lizhu et al. (2013) HCN4 dynamically marks the first heart field and conduction system precursors. Circ Res 113:399-407
Zhuang, Shaowei; Zhang, Qingquan; Zhuang, Tao et al. (2013) Expression of Isl1 during mouse development. Gene Expr Patterns 13:407-12
Peng, Tien; Tian, Ying; Boogerd, Cornelis J et al. (2013) Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor. Nature 500:589-92
Boogerd, Cornelis J; Evans, Sylvia M (2013) To activate or not to activate: the existential dilemma of an enhancer. Circ Res 112:985-7
Huber, Katrin; Narasimhan, Priyanka; Shtukmaster, Stella et al. (2013) The LIM-Homeodomain transcription factor Islet-1 is required for the development of sympathetic neurons and adrenal chromaffin cells. Dev Biol 380:286-98
Hunt, Darlene L; Campbell, Patrick H; Zambon, Alexander C et al. (2012) Early postmyocardial infarction survival in Murphy Roths Large mice is mediated by attenuated apoptosis and inflammation but depends on genetic background. Exp Physiol 97:102-14
Harrelson, Zachary; Kaestner, Klaus H; Evans, Sylvia M (2012) Foxa2 mediates critical functions of prechordal plate in patterning and morphogenesis and is cell autonomously required for early ventral endoderm morphogenesis. Biol Open 1:173-81

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