Sustained cardiomyocyte DNA synthesis in whole embryo cultures lacking the TSC2 gene product.
Sustained cardiomyocyte DNA synthesis in whole embryo cultures lacking the TSC2 gene product.
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在缺乏 TSC2 基因产物的全胚胎培养物中持续心肌细胞 DNA 合成。
DOI：
10.1152/ajpheart.1997.273.3.h1619
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Yeung,RS
中科院分区：
文献类型：
--
作者：
Pajak,L;Jin,F;Xiao,GH;Soonpaa,MH;Field,LJ;Yeung,RS
结节性硬化症（TSC）的特点是表现为非恶性肿瘤，可影响包括心脏在内的广泛器官。在染色体9 （TSC1）和16 （TSC2）上已鉴定出TSC致病基因。本研究考察了TSC2基因产物对心肌细胞增殖和终末分化的影响。我们利用了Eker大鼠携带种系TSC2突变的观察结果。突变（TSC2EK/+）的杂合大鼠易患肾癌，而突变（TSC2EK/EK）的纯合动物在妊娠中期在子宫内死亡。在胚期12.5天的TSC2EK/EK胚胎多次传代后，可以观察到自发收缩的心肌细胞，而TSC2EK/+或野生型胎儿则没有。TSC2EK/EK心肌细胞在多达8次传代后继续积极合成DNA。细胞学、超微结构和分子分析表明，TSC2EK/EK心肌细胞在胚胎晚期和新生儿早期保持了与正常大鼠心肌细胞相似的高度分化表型。这些结果表明，TSC2基因产物是正常心肌细胞周期退出和终末分化所必需的。
Tuberous sclerosis complex (TSC) is characterized by the appearance of nonmalignant tumors that affect a wide spectrum of organs, including the heart. TSC disease-causing genes have been identified on chromosomes 9 (TSC1) and 16 (TSC2). This study examined the impact of the TSC2 gene product on cardiomyocyte proliferation and terminal differentiation. We took advantage of the observation that Eker rats carry a germ-line TSC2 mutation. Rats heterozygous for the mutation (TSC2EK/+) are predisposed to renal carcinoma, whereas animals homozygous for the mutation (TSC2EK/EK) die in utero during midgestation. Spontaneously contractile cardiomyocytes were observed after multiple passages of whole embryo cultures prepared from embryonic day 12.5 TSC2EK/EK fetuses but not from TSC2EK/+ or wild-type fetuses. The TSC2EK/EK cardiomyocytes continued to actively synthesize DNA after as many as eight passages. Cytological, ultrastructural, and molecular analyses indicated that the TSC2EK/EK cardiomyocytes retained a highly differentiated phenotype similar to that observed for normal rat cardiomyocytes during late embryonic and early neonatal life. These results suggested that the TSC2 gene product is required for normal cardiomyocyte cell-cycle withdrawal and terminal differentiation.