The broad aim of this project is to dissect genetically the role of Tbx1 during pharyngeal and cardiovascular development. Tbx1 is required for the development of the pharyngeal arches and pouches and is a key candidate gene for DiGeorge Syndrome. Developmental defects of the embryonic pharyngeal apparatus are the basis of many human birth defects, including different types of congenital heart abnormalities. This project is driven by a model in which Tbx1 has an early, cell-autonomous function in pharyngeal segmentation and a later, cell non-autonomous function in the growth and remodeling of the pharyngeal arch arteries. The early function is proposed to be dependent upon genetic control of Tbx1 in the endoderm, and the late function is proposed to be dependent upon genetic interactions between Tbx1 and the fibroblast growth factor (FGF) signaling pathway. To address this model, 4 specific aims are proposed: 1) To distinguish the late from the early roles of Tbx1 by inactivating the gene in a time-controlled manner. 2) To establish the role of an endoderm enhancer of Tbx1 during pharyngeal morphogenesis, by modifying the enhancer in the endogenous gene. 3) To understand the role of the FGF signaling in the pathogenesis of the Tbx1 mutant phenotype. This will be achieved by a) testing the ability of FGF activity to rescue the Tbx1 mutant phenotype b) disrupting T-box binding sites from the Fgf8 and Fgf10 genes, and c) testing the ability of Tbx1 to activate Fgf genes ectopically. 4) To understand the role of Tbx1 in the alignment of the outflow tract using tissue-specific deletion. It is proposed that this role is also mediated by the FGF signaling. Published and preliminary data support the proposed model, and the collection of Tbx1 mutant alleles already generated and that will be generated with this project, should provide a unique opportunity to dissect the role of Tbx1 in cardiovascular and pharyngeal development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL051524-09
Application #
6729503
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Schramm, Charlene A
Project Start
1996-05-05
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
9
Fiscal Year
2004
Total Cost
$376,250
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Vitelli, Francesca; Huynh, Tuong; Baldini, Antonio (2009) Gain of function of Tbx1 affects pharyngeal and heart development in the mouse. Genesis 47:188-95
Xu, Huansheng; Baldini, Antonio (2007) Genetic pathways to mammalian heart development: Recent progress from manipulation of the mouse genome. Semin Cell Dev Biol 18:77-83
Huynh, Tuong; Chen, Li; Terrell, Phillip et al. (2007) A fate map of Tbx1 expressing cells reveals heterogeneity in the second cardiac field. Genesis 45:470-5
Dastjerdi, Akbar; Robson, Lesley; Walker, Rebecca et al. (2007) Tbx1 regulation of myogenic differentiation in the limb and cranial mesoderm. Dev Dyn 236:353-63
Zhang, Zhen; Huynh, Tuong; Baldini, Antonio (2006) Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. Development 133:3587-95
Vitelli, Francesca; Zhang, Zhen; Huynh, Tuong et al. (2006) Fgf8 expression in the Tbx1 domain causes skeletal abnormalities and modifies the aortic arch but not the outflow tract phenotype of Tbx1 mutants. Dev Biol 295:559-70
Xu, Huansheng; Cerrato, Fabiana; Baldini, Antonio (2005) Timed mutation and cell-fate mapping reveal reiterated roles of Tbx1 during embryogenesis, and a crucial function during segmentation of the pharyngeal system via regulation of endoderm expansion. Development 132:4387-95
Zhang, Zhen; Cerrato, Fabiana; Xu, Huansheng et al. (2005) Tbx1 expression in pharyngeal epithelia is necessary for pharyngeal arch artery development. Development 132:5307-15
Xu, Huansheng; Morishima, Masae; Wylie, John N et al. (2004) Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development 131:3217-27
Morishima, Masae; Yanagisawa, Hiromi; Yanagisawa, Masashi et al. (2003) Ece1 and Tbx1 define distinct pathways to aortic arch morphogenesis. Dev Dyn 228:95-104

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