共查询到20条相似文献,搜索用时 15 毫秒
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TBX20 gain-of-function mutations in humans are associated with congenital heart malformations and myocardial defects. However the effects of increased Tbx20 function during cardiac chamber development and maturation have not been reported previously. CAG-CAT-Tbx20 transgenic mice were generated for Cre-dependent induction of Tbx20 in myocardial lineages in the developing heart. βMHCCre-mediated overexpression of Tbx20 in fetal ventricular cardiomyocytes results in increased thickness of compact myocardium, induction of cardiomyocyte proliferation, and increased expression of Bmp10 and pSmad1/5/8 at embryonic day (E) 14.5. βMHCCre-mediated Tbx20 overexpression also leads to increased expression of cardiac conduction system (CCS) genes Tbx5, Cx40, and Cx43 throughout the ventricular myocardium. In contrast, Nkx2.5Cre mediated overexpression of Tbx20 in the embryonic heart results in reduced cardiomyocyte proliferation, increased expression of a cell cycle inhibitor, p21(CIP1), and decreased expression of Tbx2, Tbx5, and N-myc1 at E9.5, concomitant with decreased phospho-ERK1/2 expression. Together, these analyses demonstrate that Tbx20 differentially regulates cell proliferation and cardiac lineage specification in embryonic versus fetal cardiomyocytes. Induction of pSmad1/5/8 at E14.5 and inhibition of dpERK expression at E9.5 are consistent with selective Tbx20 regulation of these pathways in association with stage-specific effects on cardiomyocyte proliferation. Together, these in vivo data support distinct functions for Tbx20 in regulation of cardiomyocyte lineage maturation and cell proliferation at embryonic and fetal stages of heart development. 相似文献
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The recent discovery of several myogenic cardiac progenitor cells in the post-natal heart suggests that some myocardial cells may remain undifferentiated during embryonic development. In this study, we examined the subcellular characteristics of the embryonic (E) mouse ventricular myocardial cells using transmission electron microscopy (TEM). At the ultrastructural level, we identified three different cell populations within the myocardial layer of the E11.5 heart. These cells were designated as undifferentiated cells (43 +/- 6%), moderately differentiated cells (43 +/- 2%) and mature cardiomyocytes (14 +/- 4%). Undifferentiated cells contained a large nucleus and sparse cytoplasm with no myofibrillar bundles. Moderately differentiated cells contained randomly arranged myofilaments in the cytoplasm. In contrast, mature cardiomyocytes contained well-developed sarcomere structures. We also confirmed the presence of similar undifferentiated cells albeit at low levels in the E16.5 ( approximately 20%) and E18.5 ( approximately 7%) myocardium. Further we used immunogold labeling technique to test whether these distinct cell populations were also positive for markers such as Nkx2.5, ISL1 and ANF. A preponderance of anti-Nkx2.5 label was found in the undifferentiated and moderately differentiated cell types. Anti-ANF label was found only in the cytoplasmic compartment of moderately differentiated and mature myocardial cells. All of the undifferentiated cells were negative for anti-ANF labeling. We did not find immuno-gold labeling with ISL1 in any of the three myocardial cell types. Based on these results, we suggest that embryonic myocardial cell differentiation is a gradual process and undifferentiated cells expressing Nkx2.5 in post-chamber myocardium may represent a progenitor cell population while cells expressing Nkx2.5 and ANF represent differentiating myocytes. 相似文献
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Up-regulation of natriuretic peptides in the ventricle of Csx/Nkx2-5 transgenic mice 总被引:3,自引:0,他引:3
Takimoto E Mizuno T Terasaki F Shimoyama M Honda H Shiojima I Hiroi Y Oka T Hayashi D Hirai H Kudoh S Toko H Kawamura K Nagai R Yazaki Y Komuro I 《Biochemical and biophysical research communications》2000,270(3):1074-1079
A cardiac homeobox-containing gene Csx/Nkx2-5, which is essential for cardiac development, is abundantly expressed in the adult heart as well as in the heart primordia. Targeted disruption of this gene results in embryonic lethality due to abnormal heart morphogenesis. To elucidate the role of Csx/Nkx2-5 in the adult heart, we generated transgenic mice which overexpress human Csx/Nkx2-5. The transgene was expressed abundantly in the heart and the skeletal muscle. mRNA levels of several cardiac genes including natriuretic peptides, CARP, MLC2v, and endogenous Csx/Nkx2-5 were increased in the ventricle of the transgenic mice. Electron microscopic analysis revealed that the ventricular myocardium of the transgenic mice had many secretory granules, which disappeared after administration of vasopressin. These results suggest that Csx/Nkx2-5 regulates many cardiac genes and induces formation of secretory granules in the adult ventricle. 相似文献
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Inna Sabirzhanova Boris Sabirzhanov Joy Bjordahl Jessica Brandt Patrick Y. Jay Timothy G. Clark 《Development, growth & differentiation》2009,51(4):403-410
Mammalian Tolloid‐like 1 (Tll‐1) is a pleiotropic metalloprotease that is expressed by a small subset of cells within the precardiac mesoderm and is necessary for proper heart development. Following heart tube formation Tll‐1 is expressed by the endocardium and regions of myocardium overlying the region of the muscular interventricular septum. Mutations in Tll‐1 lead to embryonic lethality due to cardiac defects. We demonstrate that the Tll‐1 promoter contains Nkx2–5 binding sites and that the Tll‐1 promoter is activated by and directly binds Nkx2–5. Tll‐1 expression is ablated by a dominant negative Nkx2–5 or by mutation of the Nkx2–5 binding sites within the Tll‐1 promoter. In vivo, Tll‐1 expression is decreased in the hearts of Nkx2–5 knockout embryos when compared with hemizygous and wild‐type embryos. These results show that Nkx2–5 is a direct activator of Tll‐1 expression and provide insight into the mechanism of the defects found in both the Tll‐1 and Nkx2–5 knockout mice. 相似文献
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Nkx2.5 is a cardiac specific homeobox gene critical for normal heart development. We previously identified Nkx2.5 as a target of sumoylation, a posttranslational modification implicated in a variety of cellular activities. Sumoylation enhanced Nkx2.5 activity via covalent attachment to the lysine residue 51, the primary SUMO acceptor site. However, how sumoylation regulates the activity of Nkx2.5 in vivo remains unknown. We generated transgenic mice overexpressing sumoylation deficient mutant K51R (conversion of lysine 51 to arginine) specifically in mouse hearts under the control of cardiac α-myosin heavy chain (α-MHC) promoter (K51R-Tg). Expression of the Nkx2.5 mutant transgene in the wild type murine hearts did not result in any overt cardiac phenotype. However, in the presence of Nkx2.5 haploinsufficiency, cardiomyocyte-specific expression of the Nkx2.5 K51R mutant led to congenital heart diseases (CHDs), accompanied with decreased cardiomyocyte proliferation. Also, a number of human CHDs-associated Nkx2.5 mutants exhibited aberrant sumoylation. Our work demonstrates that altered sumoylation status may underlie the development of human CHDs associated with Nkx2.5 mutants. 相似文献
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GATA4 is a dosage-sensitive regulator of cardiac morphogenesis 总被引:15,自引:0,他引:15
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Genead R Fischer H Hussain A Jaksch M Andersson AB Ljung K Bulatovic I Franco-Cereceda A Elsheikh E Corbascio M Smith CI Sylvén C Grinnemo KH 《PloS one》2012,7(5):e36804
To explore how cardiac regeneration and cell turnover adapts to disease, different forms of stress were studied for their effects on the cardiac progenitor cell markers c-Kit and Isl1, the early cardiomyocyte marker Nkx2.5, and mast cells. Adult female rats were examined during pregnancy, after myocardial infarction and ischemia-reperfusion injury with/out insulin like growth factor-1(IGF-1) and hepatocyte growth factor (HGF). Different cardiac sub-domains were analyzed at one and two weeks post-intervention, both at the mRNA and protein levels. While pregnancy and myocardial infarction up-regulated Nkx2.5 and c-Kit (adjusted for mast cell activation), ischemia-reperfusion injury induced the strongest up-regulation which occurred globally throughout the entire heart and not just around the site of injury. This response seems to be partly mediated by increased endogenous production of IGF-1 and HGF. Contrary to c-Kit, Isl1 was not up-regulated by pregnancy or myocardial infarction while ischemia-reperfusion injury induced not a global but a focal up-regulation in the outflow tract and also in the peri-ischemic region, correlating with the up-regulation of endogenous IGF-1. The addition of IGF-1 and HGF did boost the endogenous expression of IGF and HGF correlating to focal up-regulation of Isl1. c-Kit expression was not further influenced by the exogenous growth factors. This indicates that there is a spatial mismatch between on one hand c-Kit and Nkx2.5 expression and on the other hand Isl1 expression. In conclusion, ischemia-reperfusion injury was the strongest stimulus with both global and focal cardiomyocyte progenitor cell marker up-regulations, correlating to the endogenous up-regulation of the growth factors IGF-1 and HGF. Also pregnancy induced a general up-regulation of c-Kit and early Nkx2.5+ cardiomyocytes throughout the heart. Utilization of these pathways could provide new strategies for the treatment of cardiac disease. 相似文献
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