Identification of downstream genetic pathways of Tbx1 in the second heart field
- 作者：Jun Liao ; Vimla S. Aggarwal ; Sonja Nowotschin ; Alexei Bondarev ; Shari Lipner ; Bernice E. Morrow
- 关键词：Tbx1 ; Second heart field ; VCFS/DGS ; Gene expression profiling
- 刊名：Developmental Biology
- 出版年：2008
- 期刊代码：167_00121606
- 类别：bio
- 出版时间：15 April 2008
- 卷：316
- 期：2
- 页码：524-537
- 文件大小：1826 K
摘要
<i>Tbx1i>, a T-box transcription factor, and an important gene for velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) in humans, causes outflow tract (OFT) heart defects when inactivated in the mouse. <i>Tbx1i> is expressed in the second heart field (SHF) and is required in this tissue for OFT development. To identify <i>Tbx1i> regulated genetic pathways in the SHF, we performed gene expression profiling of the caudal pharyngeal region in <i>Tbx1i>−/− and wild type embryos. <i>Isl1i>, a key marker for the SHF, as well as <i>Hodi> and <i>Nkx2-6i>, were downregulated in <i>Tbx1i>−/− mutants, while genes required for cardiac morphogenesis, such as <i>Raldh2i>, <i>Gata4i>, and <i>Tbx5i>, as well as a subset of muscle contractile genes, signifying myocardial differentiation, were ectopically expressed. Pan-mesodermal ablation of <i>Tbx1i> resulted in similar gene expression changes, suggesting cell-autonomous roles of <i>Tbx1i> in regulating these genes. Opposite expression changes concomitant with SHF-derived cardiac defects occurred in <i>TBX1i> gain-of-function mutants, indicating that appropriate levels of <i>Tbx1i> are required for heart development. When taken together, our studies show that <i>Tbx1i> acts upstream in a genetic network that positively regulates SHF cell proliferation and negatively regulates differentiation, cell-autonomously in the caudal pharyngeal region.