2004 Fiscal Year Final Research Report Summary
Molecular pathways underlying congenital heart diseases
| Project/Area Number |
15591133
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Keio University |
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Principal Investigator |
YAMAHISHI Hiroyuki Keio University, Department of Medicine, 医学部, 専任講師 (40255500)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Congenital heart disease / 22q11.2 deletion syndrome / TBX1 / Sonic hedgehog / Forkhead / Cardiovascular development / Transcription factor / Gene regulation |
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| Research Abstract |
22q11.2 deletion syndrome(22q11DS) is the most frequent chromosomal microdeletion syndrome in humans, manifesting as congenital heart diseases, characterized by abnormal development of the aortic arch and the cardiac outflow tract, and craniofacial defects. Modeling of this deletion in mice suggests that the gene encoding the transcription factor TBX1 is a major genetic determinant in the etiology of 22q11DS. To explore the molecular mechanisms regulating Tbx1 expression, we generated transgenic mice harboring a lacZ reporter under control of genomic DNA upstream of Tbx1. We identified a genomic regulatory region that controlled the in vivo expression of Tbx1 and was responsive to signaling by the critical morphogen, sonic hedgehog(Shh). A single cis-element that recognized winged helix/forkhead box(Fox)-containing transcription factors was essential for regulation of Tbx1 transcription in the specific tissues. We provide in vivo evidence that a Shh-dependent signaling cascade is necessary for pharyngeal arch and aortic arch development and regulates expression of Foxa2 and Foxc2, respectively, which in turn directly activate Tbx1 transcription in distinct tissues through a common enhancer. These data provide insight into novel molecular mechanisms underlying the pathogenesis of 22q11DS and associated congenital heart diseases
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Research Products
(4 results)
