DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice
DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice
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DOI：
10.1016/j.ydbio.2003.10.036
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发表时间：
2004-02-15
影响因子：
2.7
通讯作者：
Yutzey, KE
中科院分区：
文献类型：
--
作者：
Lange, AW;Molkentin, JD;Yutzey, KE
唐氏综合症关键区 1 (DSCR1) 基因存在于人类 21 号染色体区域和小鼠 16 号染色体同线区域，其三体性与唐氏综合症中观察到的先天性心脏缺陷有关。 DSCR1 编码钙调神经磷酸酶/NFAT 信号转导途径中的调节蛋白。在心脏瓣膜间隔发育过程中，DSCR1 在发育中的房室瓣和半月瓣的心内膜、肌性室间隔和心室心肌中表达。人类 DSCR1 含有与外显子 4 相邻的富含 NFAT 的钙调神经磷酸酶反应元件。用与 lacZ (DSCR1(e4)/lacZ) 连接的小鼠 DSCR1 基因的同源调节区生成的转基因小鼠显示，心脏发育中的瓣膜和主动脉肺间隔的心内膜中存在基因激活，再现了内源性 DSCR1 心脏表达的特定子结构域。发育中的瓣膜心内膜中的DSCR1(e4)1 lacZ表达与NFATcl共定位，并且心内膜DSCR1(e4)/lacZ在NFATcl(-/-)胚胎中显着减少或缺失。此外，在NFATc1(-/-)心脏流出道中内源性DSCR1(e4)亚型的表达降低，并且在细胞培养物中DSCR1(e4)基因内元件被NFATc1反式激活。在 16 三体 (Ts16) 小鼠中，内源性 DSCR1 和 DSCR1(e4)/lacZ 的表达与异常瓣膜间隔发育共定位，并且转基因 Ts16 心脏的 β-半乳糖苷酶活性增加。 DSCR1 和 DSCR1(e4)/lacZ 也在受小鼠 16 三体性或人类 21 三体性影响的其他器官系统中表达，包括大脑、眼睛、耳朵、面部和四肢。总之，这些结果表明，发育中的瓣膜心内膜中的 DSCR1(e4) 表达依赖于 NFATcl，并支持 DSCR1 在正常心脏瓣膜间隔形成以及唐氏综合症个体中受影响的多个器官系统的异常发育中的作用。 (C) 2003 Elsevier Inc. 保留所有权利。
The Down syndrome critical region 1 (DSCR1) gene is present in the region of human chromosome 21 and the syntenic region of mouse chromosome 16, trisomy of which is associated with congenital heart defects observed in Down syndrome. DSCR1 encodes a regulatory protein in the calcineurin/NFAT signal transduction pathway. During valvuloseptal development in the heart, DSCR1 is expressed in the endocardium of the developing atrioventricular and semilunar valves, the muscular interventricular septum, and the ventricular myocardium. Human DSCR1 contains an NFAT-rich calcineurin-responsive element adjacent to exon 4. Transgenic mice generated with a homologous regulatory region of the mouse DSCR1 gene linked to lacZ (DSCR1(e4)/lacZ) show gene activation in the endocardium of the developing valves and aorticopulmonary septum of the heart, recapitulating a specific subdomain of endogenous DSCR1 cardiac expression. DSCR1(e4)1 lacZ expression in the developing valve endocardium colocalizes with NFATcl and, endocardial DSCRl(e4)/lacZ, is notably reduced or absent in NFATcl(-/-) embryos. Furthermore, expression of the endogenous DSCR1(e4) isoform is decreased in the outflow tract of NFATc1(-/-) hearts, and the DSCR1(e4) intragenic element is trans-activated by NFATc1 in cell culture. In trisomy 16 (Ts16) mice, expression of endogenous DSCR1 and DSCR1(e4)/lacZ colocalizes with anomalous valvuloseptal development, and transgenic Ts16 hearts have increased beta-galactosidase activity. DSCR1 and DSCR1(e4)/lacZ also are expressed in other organ systems affected by trisomy 16 in mice or trisomy 21 in humans including the brain, eye, ear, face, and limbs. Together, these results show that DSCR1(e4) expression in the developing valve endocardium is dependent on NFATcl and support a role for DSCR1 in normal cardiac valvuloseptal formation as well as the abnormal development of several organ systems affected in individuals with Down syndrome. (C) 2003 Elsevier Inc. All rights reserved.