Tbx3在窦房结发育和功能维持中的作用
摘要
目的综述Tbx3基因在心脏窦房结(Sinoatrial node,SN)发育和功能维持中的作用,并展望其应用前景。方法广泛查阅近十年来关于Tbx3基因对于心脏的相关文献,分析其在窦房结发育过程中及成熟后功能维持方面的调控作用,以期理清其调控网络,并对此进行综述。结果研究表明,Tbx3能抑制干细胞向心肌工作细胞分化,上调起搏细胞的表达,同时促进胚胎干细胞向窦房结样细胞分化,增强并维持起搏相关基因的表达,但Tbx3仅仅在传导系统的发育中起着"开关"的作用,其上下游及等时空位点可能还存在复杂的调控机制有待阐明。结论 Tbx3是窦房结发育和功能维持过程中非常重要的调控因子,对Tbx3的深入研究,有利于更深入了解起搏细胞发育的调控网络,可能作为缓慢型心律失常的治疗靶点之一,同时也为生物起搏器的研究提供更坚实的理论基础。
引文
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[18]BOOGERD CJ,WONG L YE,BAKKER ML,et al.Sox4mediates Tbx3 transcriptional regulation of the gap junction protein Cx43[J].Cell Mol Life Sci,2011,68(23):3949-3961.
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[20]VAN DEN BOOGAARD M,WONG LY,TESSADORI F,et al.Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer.[J].J Clin Invest,2012,122(7):2519-2530.
[21]ZHU WZ,XIE Y,MOYES KW,et al.Neuregulin/Erb B signaling regulates cardiac subtype specification in differentiating human embryonic stem cells[J].Circ Res,2010,107(6):776-786.
[2]GREULICH F,RUDAT C,KISPERT A.Mechanisms of T-box gene function in the developing heart[J].Cardiovasc Res,2011,91(2):212-222.
[3]TADA M,SMITH JC.T-targets:clues to understanding the functions of T-box proteins[J].Dev Growth Differ,2001,43(1):1-11.
[4]HOOGAARS WM,BARNETT P,RODRIGUEZ M,et al.Tbx3 and its splice variant Tbx3+exon 2a are functionally similar[J].Pigment Cell Melanoma Res,2008,21(3):379-387.
[5]DAVENPORT TG,JEROME-MAJEWSKA LA,PAPAIOANNOU VE.Mammary gland,limb and yolk sac defects in mice lacking Tbx3,the gene mutated in human ulnar mammary syndrome[J].Development,2003,130(10):2263-2273.
[6]WASHKOWITZ AJ,GAVRILOV S,BEGUM S,et al.Diverse functional networks of Tbx3 in development and disease[J].Wiley Interdiscip Rev Syst Biol Med,2012,4(3):273-283.
[7]CHRISTOFFELS VM,MOORMAN AF.Development of the cardiac conduction system why are some regions of the heart more arrhythmogenic than others?[J].Circ Arrhythmia Electrophysiol,2009,2(2):195-207.
[8]AANHAANEN WT,MOMMERSTEEG MT,NORDEN J,et al.Developmental origin,growth,and three-dimensional architecture of the atrioventricular conduction axis of the mouse heart[J].Circ Res,2010,107(6):728-736.
[9]HOOGAARS WM,ENGEL A,BRONS JF,et al.Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria[J].Genes Dev,2007,21(9):1098-1112.
[10]乔爱秀.胚胎心脏传导系统的发育[D].太原:山西医科大学基础医学院,2012.
[11]O'RAHILLY R,MüLLER F.Developmental stages in human embryos:revised and new measurements[J].Cells Tissues Organs,2010,192(2):73-84.
[12]CHRISTOFFELS VM,SMITS GJ,KISPERT A,et al.Development of the pacemaker tissues of the heart[J].Circ Res,2010,106(2):240-254.
[13]BAKKER ML,BOUKENS BJ,MOMMERSTEEG MT,et al.Transcription factor Tbx3 is required for the specification of the atrioventricular conduction system[J].Circ Res,2008,102(11):1340-1349.
[14]WIESE C,GRIESKAMP T,AIRIK R,et al.Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3[J].Circ Res,2009,104(3):388-397.
[15]BLASCHKE RJ,HAHURIJ ND,KUIJPER S,et al.Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development[J].Circulation,2007,115(14):1830-1838.
[16]ESPINOZA-LEWIS RA,YU L,HE F,et al.Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2.5[J].Dev Biol,2009,327(2):376-385.
[17]BOGARAPU S,BLEYL SB,CALHOUN A,et al.Everitt and D.U.Frank.Phenotype of a patient with contiguous deletion of TBX5 and TBX3:expanding the disease spectrum[J].American Journal of Medical Genetics Part A,2014,164A(5):1304-1309.
[18]BOOGERD CJ,WONG L YE,BAKKER ML,et al.Sox4mediates Tbx3 transcriptional regulation of the gap junction protein Cx43[J].Cell Mol Life Sci,2011,68(23):3949-3961.
[19]FRANK DU,CARTERA KL,THOMAS KR,et al.Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis[J].Proc Natl Acad Sci USA,2012,109(3):E154-163.
[20]VAN DEN BOOGAARD M,WONG LY,TESSADORI F,et al.Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer.[J].J Clin Invest,2012,122(7):2519-2530.
[21]ZHU WZ,XIE Y,MOYES KW,et al.Neuregulin/Erb B signaling regulates cardiac subtype specification in differentiating human embryonic stem cells[J].Circ Res,2010,107(6):776-786.