Lange Alexander W, Molkentin Jeffery D, Yutzey Katherine E
Division of Molecular Cardiovascular Biology, Children's Medical Center Cincinnati ML 7020, Cincinnati, OH 45229, USA.
Dev Biol. 2004 Feb 15;266(2):346-60. doi: 10.1016/j.ydbio.2003.10.036.
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)/lacZ expression in the developing valve endocardium colocalizes with NFATc1 and, endocardial DSCR1(e4)/lacZ, is notably reduced or absent in NFATc1(-/-) 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 NFATc1 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.
唐氏综合征关键区域1（DSCR1）基因位于人类21号染色体区域以及小鼠16号染色体的同区域，该区域的三体性与唐氏综合征中观察到的先天性心脏缺陷相关。DSCR1在钙调神经磷酸酶/NFAT信号转导通路中编码一种调节蛋白。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、肌性室间隔以及心室心肌中表达。人类DSCR1在第4外显子附近含有一个富含NFAT的钙调神经磷酸酶反应元件。用与lacZ相连的小鼠DSCR1基因的同源调控区域产生的转基因小鼠（DSCR1(e4)/lacZ）显示，在发育中的心脏瓣膜和主动脉肺动脉间隔的心内膜中有基因激活，重现了内源性DSCR1心脏表达的一个特定亚域。发育中的瓣膜心内膜中DSCR1(e4)/lacZ的表达与NFATc1共定位，并且在NFATc1(-/-)胚胎中，心内膜DSCR1(e4)/lacZ明显减少或缺失。此外，内源性DSCR1(e4)异构体在NFATc1(-/-)心脏的流出道中表达降低，并且DSCR1(e4)基因内元件在细胞培养中被NFATc1反式激活。在16三体（Ts16）小鼠中，内源性DSCR1和DSCR1(e4)/lacZ的表达与异常的瓣膜间隔发育共定位，并且转基因Ts16心脏具有增加的β-半乳糖苷酶活性。DSCR1和DSCR1(e4)/lacZ也在受小鼠16三体或人类21三体影响的其他器官系统中表达，包括脑、眼、耳、面部和四肢。总之，这些结果表明发育中的瓣膜心内膜中DSCR1(e4)的表达依赖于NFATc1，并支持DSCR1在正常心脏瓣膜间隔形成以及唐氏综合征患者中受影响的几个器官系统的异常发育中发挥作用。
