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骨形态发生蛋白-2在小鼠胚胎心流出道发育中的作用
屈旭宽 洪肖杨 景雅 杨艳萍 许智慧 崔慧林 乔从进 李海荣*
解剖学报 ›› 2015, Vol. 46 ›› Issue (5) : 649-654.
骨形态发生蛋白-2在小鼠胚胎心流出道发育中的作用
Contributions of bone morphogenetic protein -2 to a cardiac outflow tract in the development of the mouse embryo
目的 探讨骨形态发生蛋白-2(BMP-2)在小鼠胚胎心流出道发育过程中的作用。 方法 对胚龄9d(E9) ～E15（各胚龄取3～7只）小鼠心连续石蜡切片，用抗α-横纹肌肌动蛋白(α-SCA)抗体、抗胰岛素增强子结合蛋白(ISL-1)抗体、抗增殖细胞核抗原(PCNA)抗体、抗BMP-2抗体进行免疫组织化学染色。结果 E9，流出道心胶质内无细胞，心肌增殖活性低，BMP-2弱表达于流出道心肌、心内膜及心包腔背侧壁。E9～11，流出道增长，心包腔背侧壁ISL-1阳性细胞至流出道远端分化为心肌细胞后增殖逐渐减弱。E10～11，流出道嵴内间充质细胞逐渐增加，可见BMP-2、PCNA阳性细胞；流出道BMP-2表达逐渐增强达高峰，向两端延伸逐渐减弱，动脉端可及心包反折处。E12，流出道缩短，BMP-2表达减弱。E13～15，流出道隔逐渐肌化，BMP-2在心脏近大血管部心肌呈较弱表达。E10～13，流出道远段心肌呈低增殖活性，近段及右心室心肌增殖成小梁致右心室形成及扩大。结论 BMP-2诱导第二生心区(SHF)细胞分化为心肌细胞添加至心动脉端，参与心流出道嵴的发育。BMP-2抑制流出道心肌增殖，流出道近段BMP2表达减弱重启了心肌细胞增殖，致右心室形成及流出道缩短。低水平的BMP2可能诱导流出道隔间充质细胞向心肌分化。
Objective To explore the contribution of bone morphogenetic protein-2 (BMP-2) in the development of the cardiac outflow tract(OFT) of the mouse embryo.
Methods Serial paraffin sections of mouse embryonic hearts from embryonic day 9(E9) to E15 were stained with antibodies against α-sarcomeric actin(α-SCA), islet-1(ISL-1), proliferating cell nuclear antigen(PCNA) or BMP-2 by the immunohistochemical method. Three to seven mice were examined for each stage. Results At E9, no cell was observed in the cardiac jelly of OFT. Scarce PCNA expressing cells were found in OFT myocardium. Weak BMP-2 expressed in the OFT myocardium, endocardium and dorsal pericardium. During E9-11, with the addition of cardiomyocytes derived from the second heart field to the arterial pole, the OFT lengthened. The proliferation rate of these newly added cells dropped gradually during recruitment into the OFT. During E10-11, mesenchymal cells gradually filled the OFT ridges, some of them expressing BMP-2, PCNA. BMP-2 expression in myocardium of OFT was up-regulated to the peak at the stages and tapered off toward the poles, reaching up to the reflection of pericardium at the arterial pole. At E12, the OFT shortened and its BMP-2 expression level was down-regulated. During E13-15, the mesenchymal outlet septum were gradually myocardialized and weak BMP-2 expression was restricted to the OFT myocardium adjacent to the great vessels. During E10~13, myocardium of the distal OFT showed low proliferation activity while myocardium of the proximal OFT and right ventricle proliferated into trabeculae and resulted in the development of right ventricle. Conclusion BMP-2 induceds the precursors from the second heart field to differentiate into cardiomyocytes and add to the arterial pole of the heart. BMP-2 is participated in the development of OFT ridges. BMP-2 inhibites cardiomyocytes of OFT proliferating and its down-regulation in the proximal portion reinitiated cardiomyocytes proliferating, which leads to the development of right ventricle and shortening of the OFT. Low level of BMP-2 might induce mesenchymal cells in OFT septum to differentiate into cardiomyocytes.
胚胎 / 心流出道 / 骨形态发生蛋白-2 / 增殖细胞核抗原 / 胰岛素增强子结合蛋白 / 免疫组织化学 / 小鼠
Embryo / Cardiac outflow tract / Bone morphogenetic protein-2 / Proliferating cell nuclear antigen / Islet-1 / Immunohistochemistry / Mouse
［1］Wang J, Greene SB, Bonilla-Claudio M, et al. Bmp signaling regulates myocardial differentiation from cardiac progenitors through a MicroRNA-mediated mechanism［J］. Developmental Cell, 2010, 19(6): 903-912.
［2］Nomura-Kitabayashi A, Anderson GA, Sleep G, et al.Endoglin is dispensable for angiogenesis, but required for endocardial cushion formation in the midgestation mouse embryo［J］. Dev Biol, 2009, 335(1): 66-77.
［3］Liu Y, Jin Y, Li J, et al. Inactivation of Cdc42 in neural crest cells causes craniofacial and cardiovascular morphogenesis defects［J］. DevBiol, 2013, 383(2): 239-252.
［4］Feng XL, Jing Y, Li HR, et al.Expression patterns of Nkx2.5 and ISL-1 during early development of mouse embryonic heart［J］. Chinese Journal of Anatomy, 2010, 33(5): 577-594.（in Chinese）
冯先玲，景雅，李海荣，等.转录因子Nkx2.5、ISL-1表达与小鼠胚胎心的早期发育［J］. 解剖学杂志，2010，33(5): 577-594.
［5］Ma L, Lu MF, Schwartz RJ, et al.Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning［J］. Development, 2005, 132(24): 5601-5611.
［6］Waldo KL, Kumiski DH, Wallis KT, et al.Conotruncal myocardium arises from a secondary heart field［J］. Development, 2001, 128(16): 3179-3188.
［7］Prall OW, Menon MK, Solloway MJ, et al.An nkx2-5/bmp2/smad1 negative feedback loop controls heart progenitor specification and proliferation［J］. Cell, 2007, 128(5): 947-959.
［8］Yelbuz TM, Waldo KL, Zhang X, et al.Myocardial volume and organization are changed by failure of addition of secondary heart field myocardium to the cardiac outflow tract［J］. Dev Dyn, 2003, 228(2): 152-160.
［9］Waldo KL, Hutson MR, Stadt HA, et al.Cardiac neural crest is necessary for normal addition of the myocardium to the arterial pole from the secondary heart field［J］. Dev Biol, 2005, 281(1): 66-77.
［10］Li HR, Yang YP, Wang JJ, et al.Ventricularization of the proximal cardiac outflow tract contributes to trabeculated right ventricle in mouse embryo［J］. Acta Anatomica sinica, 2014, 45(5):689-703.（in Chinese）
李海荣，杨艳萍，王晶晶，等.小鼠胚胎心流出道近段心室化形成右心室小梁部［J］. 解剖学报，2014，45(5): 689-703.
［11］Singh R, Kispert A.Tbx20, Smads, and the atrioventricular canal［J］. Cardiovascular Medicine, 2010, 20(4): 109-114.
［12］De Pater E, Ciampricotti M, Priller F, et al.Bmp signaling exerts opposite effects on cardiac differentiation［J］. Circ Res, 2012, 110(4): 578-587.
［13］Van den Hoff MJ, Moorman AF, Ruijter JM, et al.Myocardialization of the cardiac outflow tract［J］. Dev Biol, 1999, 212(2): 477-490.
［14］Waller BR 3rd, McQuinn T, Phelps AL, et al.Conotruncal anomalies in the trisomy 16 mouse: an immunohistochemical analysis with emphasis on the involvement of the neural crest［J］. Anat Rec, 2000, 260(3): 279-293.
［15］Luna-Zurita L, Prados B, Grego-Bessa J, et al.Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation［J］. J Clin Invest, 2010, 120(10): 3493-3507.
［16］Correia AC, Costa M, Moraes F, et al.Bmp2 is required for migration but not for induction of neural crest cells in the mouse［J］. Dev Dyn, 2007, 236(9): 2493-2501.
［17］Allen SP, Bogardi JP, Barlow AJ, et al.Misexpression of noggin leads to septal defects in the outflow tract of the chick heart［J］. Dev Biol, 2001, 235(1): 98-109.
［18］Délot EC, Bahamonde ME, Zhao M, et al.BMP signaling is required for septation of the outflow tract of the mammalian heart［J］. Development, 2003, 130(1): 209220.
［19］Qi LH, Jing Y, Cao XM, et al.Expresssion patterns of transforming growth factors during development of mollse embryonic heart［J］. Chinese Journal of Anatomy, 2005, 28(1):34-36.（in Chinese）
祁丽华，景雅，曹锡梅，等.小鼠胚胎心脏发育过程中转化生长因子的表达特点［J］. 解剖学杂志，2005，28(1): 34-36.
［20 Liu HX, Jing YX, Guo JJ, et al.Spatiotemporal expression patterns of transforming growth factor TGFp srecePtors TpR IandTpRll during the development of embryonic mouse heart［J］. Acta Anatomica Sinica, 2009, 40(6):954-947.（in Chinese）
刘慧霞，景宜馨，郭健津，等.小鼠胚胎心脏发育过程中转化生长因子受体TβRⅠ、TβRⅡ的表达特点［J］. 解剖学报，2009，40(6): 954-947.
［21］Bartram U, Molin DG, Wisse LJ, et al.Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping,myocardialization, endocardial cushion differentiation, and apoptosis in TGF-beta(2)-knockout mic［J］. Circulation. 2001, 103(22): 2745-2752.
［22］Zhao XQ, Huang GY, Xie LJ, et al.The role of TGFβ2 in myocardialization of cardiac proximal outflow tract septum in mice［J］. Acta Anatomica Sinica, 2003, 37(2): 190-194.（in Chinese）
赵晓晴， 黄国英， 谢利剑，等.转化生长因子β2在小鼠心脏近端流出道隔心肌化过程中的作用［J］. 解剖学报，2003，37(2):190-194.
［23］Chen WCh, Zhang Y, Huang GY, et al.Key genes in the myocardialization of proximal cardiac outflow tract septum in Cx43 knockout mice［J］. Fudan University Journal of Medical Sciences, 2010, 37(1):52-58.（in Chinese）
陈伟呈，张颖， 黄国英，等.Cx43基因敲除胎鼠心脏近端流出道隔心肌化过程中的关键基因［J］. 复旦学报（医学版），2010，37(1):52-58.
［24］Chen WC, Zhang Y, Ma D, et al.Bmp2 regulates the interaction between EPDCs and myocytes in cardiac OFT［J］. Med Hypotheses, 2012, 79(2): 174-177.
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