Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5.
Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5.
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DOI：
10.1016/j.ydbio.2008.12.028
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发表时间：
2009-03-15
影响因子：
2.7
通讯作者：
Chen, YiPing
中科院分区：
文献类型：
--
作者：
Espinoza-Lewis, Ramon A.;Yu, Ling;He, Fenglei;Liu, Hongbing;Tang, Ruhang;Shi, Jiangli;Sun, Xiaoxiao;Martin, James F.;Wang, Dazhi;Yang, Jing;Chen, YiPing
起搏器由位于窦房结（SAN）内的特化心肌细胞组成，负责发起和调节心跳。最近的进展对理解SAN的发展已经取得了遗传控制和基因相互作用在这个结构。在这里，我们报告说，Shox 2同源结构域转录因子是有限的表达在静脉窦区域，包括SAN和窦瓣膜在胚胎心脏发育。Shox 2无效突变导致由于心血管缺陷导致的胚胎死亡，包括异常低心率（心动过缓）和归因于细胞增殖水平显著降低的严重发育不全的SAN和窦瓣。从遗传学上讲，Tbx 3和Hcn 4表达的缺乏，以及Shox 2 −/− SAN区域中Nppa、Cx40和Nkx 2 -5的异位激活沿着，表明SAN分化失败。此外，Shox 2在非洲爪蟾胚胎中的过表达导致发育中的心脏中Nkx 2 -5的广泛抑制，从而导致减少的心脏场和异常的心脏形成。报告基因表达测定为Shox 2抑制Nkx 2 -5启动子活性提供了额外的证据。总之，我们的研究结果表明，Shox 2通过抑制Nkx 2 -5控制遗传级联反应，在SAN和起搏器的发展中起着至关重要的作用。
The pacemaker is composed of specialized cardiomyocytes located within the sinoatrial node (SAN), and is responsible for originating and regulating the heart beat. Recent advances towards understanding the SAN development have been made on the genetic control and gene interaction within this structure. Here we report that the Shox2 homeodomain transcription factor is restrictedly expressed in the sinus venosus region including the SAN and the sinus valves during embryonic heart development. Shox2 null mutation results in embryonic lethality due to cardiovascular defects, including an abnormal low heart beat rate (bradycardia) and severely hypoplastic SAN and sinus valves attributed to a significantly decreased level of cell proliferation. Genetically, the lack of Tbx3 and Hcn4 expression, along with ectopic activation of Nppa, Cx40, and Nkx2-5 in the Shox2−/− SAN region, indicates a failure in SAN differentiation. Furthermore, Shox2 overexpression in Xenopus embryos results in extensive repression of Nkx2-5 in the developing heart, leading to a reduced cardiac field and aberrant heart formation. Reporter gene expression assays provide additional evidence for the repression of Nkx2-5 promoter activity by Shox2. Taken together our results demonstrate that Shox2 plays an essential role in the SAN and pacemaker development by controlling a genetic cascade through the repression of Nkx2-5.
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影响因子：
10.5
作者：
Hoogaars, Willem M. H.;Engel, Angela;Christoffels, Vincent M.
通讯作者：
Christoffels, Vincent M.
DOI：
10.1152/physiologyonline.2002.17.1.32
发表时间：
2002-02-01
期刊：
NEWS IN PHYSIOLOGICAL SCIENCES
影响因子：
--
作者：
Accili, EA;Proenza, C;DiFrancesco, D
通讯作者：
DiFrancesco, D
DOI：
10.1159/000056782
发表时间：
2000-01-01
期刊：
CYTOGENETICS AND CELL GENETICS
影响因子：
--
作者：
Doevendans, PA;Bronsaer, R;van Bilsen, M
通讯作者：
van Bilsen, M
Osf2/Cbfa1：成骨细胞分化的转录激活因子
影响因子：
64.5
作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G
影响因子：
64.5
作者：
Berger, Michael F.;Badis, Gwenael;Hughes, Timothy R.
通讯作者：
Hughes, Timothy R.