| Project/Area Number |
17591114
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatrics
|
|---|
| Research Institution | KEIO UNIVERSITY |
|---|
Principal Investigator |
YAMAGISHI Hiroyuki Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (40255500)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
|
|---|
| Keywords | Morphology / Differentiation / Molecular biology / Embryology / Animal medel / 先天性心疾患 / 心臓流出路 / 動脈幹 / 前方心臓領域 / Tbx1 / Forkhead / 転写因子 / 遺伝子発現 |
|---|
| Research Abstract |
Transcriptional regulation in a tissue-specific and quantitative fashion is essential for developmental events, including those involved in cardiovascular morphogenesis. Tbx1 is a T-box containing transcription factor that is essential for the cardiac outflow tract (OFT) development and is responsible for many of the defects observed in 22q11 deletion (del22q11) syndrome in humans. Here, we show that Tbx1 expression in the anterior heart field (AHF) is regulated by Fox proteins through a combination of two evolutionally conserved Fox binding sites in a dose-dependent manner. Cell fate analyses using the Tbx1 enhancer suggests that AHF-derived Tbx1-expressing cells contribute extensively to the right ventricular myocardium as well as the OFT during the early development and finally give rise to the right ventricular infundibulum, pulmonary trunk and pulmonary valves. Moreover, analyses of an allelic series of Tbx1 deficiency revealed a lower critical threshold for Tbx1 activity in the cardiac outflow tract compared to other pharyngeal arch derivatives, including the palatal bones. A Tbx1-dependent transcriptional and signaling network in the cardiac outflow tract that renders mouse cardiovascular development seemed more susceptible to reduction in Tbx1 dosage than craniofacial development, similar to humans with del22q11. Phenotype variability in human congenital cardiac outflow defect associated with del22q11 could be explained by variable reduction in Tbx1 during development that may be due to second genetic loci and/or environmental factors.
|
