Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5

被引：175

作者：

Espinoza-Lewis, Ramon A. ^{[1
]}

Yu, Ling ^{[1
]}

He, Fenglei ^{[1
]}

Liu, Hongbing ^{[1
]}

Tang, Ruhang ^{[2
]}

Shi, Jiangli ^{[3
]}

Sun, Xiaoxiao ^{[4
]}

Martin, James F. ^{[4
]}

Wang, Dazhi ^{[2
]}

Yang, Jing ^{[3
]}

Chen, YiPing ^{[1
]}

机构：

[1] Tulane Univ, Dept Cell & Mol Biol, New Orleans, LA 70118 USA

[2] Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA

[3] Nationwide Childrens Hosp, Res Inst, Ctr Cell & Dev Biol, Columbus, OH 43205 USA

[4] Texas A&M Hlth Sci Ctr, Alkek Inst Biosci & Technol, Houston, TX 77030 USA

来源：

DEVELOPMENTAL BIOLOGY | 2009年 / 327卷 / 02期

关键词：

Shox2; Nkx2-5; Sinoatrial node; Pacemaker; Sinus valves; Heart development; LIGHT CHAIN-2 EXPRESSION; HOMEOBOX GENE SHOX; TRANSCRIPTION FACTORS; SHORT-STATURE; LERI-WEILL; SINOATRIAL NODE; CHANNEL HCN4; HEART; CSX/NKX2.5; MUTATIONS;

D O I：

10.1016/j.ydbio.2008.12.028

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 Shax2 plays an essential role in the SAN and pacemaker development by controlling a genetic cascade through the repression of Nkx2-5. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：376 / 385

页数：10

共 69 条

[41] The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator [J].

Rao, E ;

Blaschke, RJ ;

Marchini, A ;

Niesler, B ;

Burnett, M ;

Rappold, GA .

HUMAN MOLECULAR GENETICS, 2001, 10 (26) :3083-3091

[42] Cloning and characterization of four murine homeobox genes [J].

Rovescalli, AC ;

Asoh, S ;

Nirenberg, M .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (20) :10691-10696

[43] Pitx2 determines left-right asymmetry of internal organs in vertebrates [J].

Ryan, AK ;

Blumberg, B ;

Rodriguez-Esteban, C ;

Yonei-Tamura, S ;

Tamura, K ;

Tsukui, T ;

de la Peña, J ;

Sabbagh, W ;

Greenwald, J ;

Choe, S ;

Norris, DP ;

Robertson, EJ ;

Evans, RM ;

Rosenfeld, MG ;

Belmonte, JCI .

NATURE, 1998, 394 (6693) :545-551

[44] The HCN gene family: Molecular basis of the hyperpolarization-activated pacemaker channels [J].

Santoro, B ;

Tibbs, GR .

MOLECULAR AND FUNCTIONAL DIVERSITY OF ION CHANNELS AND RECEPTORS, 1999, 868 :741-764

[45] Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS [J].

Santoro, B ;

Chen, S ;

Lüthi, A ;

Pavlidis, P ;

Shumyatsky, GP ;

Tibbs, GR ;

Siegelbaum, SA .

JOURNAL OF NEUROSCIENCE, 2000, 20 (14) :5264-5275

[46] If inhibition with ivabradine -: Electrophysiological effects and safety [J].

Savelieva, Irina ;

Camm, A. John .

DRUG SAFETY, 2008, 31 (02) :95-107

[47] Congenital heart disease caused by mutations in the transcription factor NKX2-5 [J].

Schott, JJ ;

Benson, DW ;

Basson, CT ;

Pease, W ;

Silberbach, GM ;

Moak, JP ;

Maron, BJ ;

Seidman, CE ;

Seidman, JG .

SCIENCE, 1998, 281 (5373) :108-111

[48] A new human homeobox gene OG12X is a member of the most conserved homeobox gene family and is expressed during heart development in mouse [J].

Semina, EV ;

Reiter, RS ;

Murray, JC .

HUMAN MOLECULAR GENETICS, 1998, 7 (03) :415-422

[49] Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis [J].

Shears, DJ ;

Vassal, HJ ;

Goodman, FR ;

Palmer, RW ;

Reardon, W ;

Superti-Furga, A ;

Scambler, PJ ;

Winter, RM .

NATURE GENETICS, 1998, 19 (01) :70-73

[50]

Sive H.L., 2000, Early Development of Xenopus laevis: a Laboratory Manual

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