This is a revised RO1 application for four years of support to identify genes in mice responsible for congenital heart disease associated with the human 22qdel syndrome. The PI has recently demonstrated that an approximately 1 Mb Cre-mediated deletion that extends between Ufd1l and Es2 causes abnormalities of 4th aortic arch derivatives very similar to those found in humans with the common 22q deletion. A duplication of the same region-recovered as a reciprocal recombination product between tandem lox sites-prevents cardiac abnormalities in duplication/deficiency heterozygotes, suggesting that haploinsufficiency for a gene or genes within the deletion is responsible for the characteristic cardiac defect. Preliminary data obtained with additional deficiencies since the last submission suggests that the sequence necessary for the 4th arch abnormality lies within a 150 kb """"""""critical region"""""""" and that complementation with a slightly larger region would be sufficient to rescue that abnormality. The sequence of the entire region has been determined. In the current application, the PI proposes to test for complementation 3 BAC or PAC clones that span the region (Aim 1). Individual candidates within a complementing BAC will be evaluated by gene targeting (Aim 2), and function of correct candidate will be investigated further by analyzing the homozygous mutant phenotype, possibly in the context of a conditional allele.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL064832-01A1
Application #
6262702
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Wang, Lan-Hsiang
Project Start
2000-12-15
Project End
2004-11-30
Budget Start
2000-12-15
Budget End
2001-11-30
Support Year
1
Fiscal Year
2001
Total Cost
$186,875
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Vitelli, Francesca; Lania, Gabriella; Huynh, Tuong et al. (2010) Partial rescue of the Tbx1 mutant heart phenotype by Fgf8: genetic evidence of impaired tissue response to Fgf8. J Mol Cell Cardiol 49:836-40
Zhang, Zhen; Baldini, Antonio (2010) Manipulation of endogenous regulatory elements and transgenic analyses of the Tbx1 gene. Mamm Genome 21:556-64
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Chen, Li; Fulcoli, Filomena Gabriella; Tang, Susan et al. (2009) Tbx1 regulates proliferation and differentiation of multipotent heart progenitors. Circ Res 105:842-51
Lania, Gabriella; Zhang, Zhen; Huynh, Tuong et al. (2009) Early thyroid development requires a Tbx1-Fgf8 pathway. Dev Biol 328:109-17
Caterino, Marianna; Ruoppolo, Margherita; Fulcoli, Gabriella et al. (2009) Transcription factor TBX1 overexpression induces downregulation of proteins involved in retinoic acid metabolism: a comparative proteomic analysis. J Proteome Res 8:1515-26
Vitelli, Francesca; Huynh, Tuong; Baldini, Antonio (2009) Gain of function of Tbx1 affects pharyngeal and heart development in the mouse. Genesis 47:188-95
Fulcoli, F Gabriella; Huynh, Tuong; Scambler, Peter J et al. (2009) Tbx1 regulates the BMP-Smad1 pathway in a transcription independent manner. PLoS One 4:e6049
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

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