Scaffold attachment factor B1 functions in development, growth, and reproduction
Scaffold attachment factor B1 functions in development, growth, and reproduction
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DOI：
10.1128/mcb.25.8.2995-3006.2005
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发表时间：
2005-04-01
影响因子：
5.3
通讯作者：
Oesterreich, S
中科院分区：
文献类型：
--
作者：
Ivanova, M;Dobrzycka, KM;Oesterreich, S
支架附着因子B1（SAFB 1）是一种多功能蛋白质，可以结合DNA和RNA，并参与RNA加工和应激反应。此外，SAFB 1含有转录抑制结构域，可以结合某些激素受体并抑制其活性。为了评估SAFB 1在体内的作用，我们通过在胚胎干细胞中靶向缺失来产生SAFB 1突变小鼠。虽然获得了存活的纯合突变（SAFB 1（-/-））小鼠，但基因型分布表明纯合缺陷导致产前和新生儿致死。缺乏SAFB 1的小鼠表现出侏儒症，这是子宫内生长迟缓的结果，并且具有低血清胰岛素样生长因子1（IGF 1）水平。与先前SAFB 1作为激素受体辅阻遏物的特征一致，我们发现SAFB 1（-/-）小鼠在生殖系统的发育和功能方面表现出显着的缺陷。雄性SAFB 1基因敲除小鼠不育，显然是因为低循环水平的睾酮。SAFB 1（-/-）睾丸较小，生殖上皮进行性变性，生殖细胞凋亡增加，间质细胞增生。SAFB（-/-）雌性小鼠生育力低下，表现出进行性不孕，部分原因是输卵管运输缺陷和卵泡数量减少。永生化的SAFB 1（-/-）小鼠胚胎成纤维细胞表现出细胞内在缺陷，包括增加转录雌激素受体et活性和增强对IGF 1的反应性。总之，这些体内发现确立了SAFB 1在发育、生长调节和生殖中的关键作用。
Scaffold attachment factor B1 (SAFB1) is a multifunctional protein that can bind both DNA and RNA and is involved in RNA processing and stress response. In addition, SAFB1 contains a transcriptional repression domain and can bind certain hormone receptors and repress their activity. To assess the role of SAFB1 in vivo, we generated SAFB1 mutant mice through targeted deletion in embryonic stem cells. While viable homozygous mutant (SAFB1(-/-)) mice were obtained, genotypic distribution indicated that homozygous deficiency resulted in both prenatal and neonatal lethality. Mice lacking SAFB1 exhibited dwarfism, as a result of in utero growth retardation, and had low serum insulin-like growth factor 1 (IGF1) levels. In agreement with the previous characterization of SAFB1 as a corepressor for hormone receptors, we found that SAFB1(-/-) mice displayed dramatic defects in the development and function of the reproductive system. Male SAFB1 null mice were infertile, apparently because of low circulating levels of testosterone. SAFB1(-/-) testes were small and showed progressive degeneration of the germinal epithelium, increased apoptosis of germ cells, and Leydig cell hyperplasia. SAFB(-/-) female mice were subfertile and showed progressive infertility, in part because of defects in oviductal transport and reduced numbers of follicles. Immortalized SAFB1(-/-) mouse embryonic fibroblasts showed cell-intrinsic defects including increased transcriptional estrogen receptor et activity and enhanced responsiveness to IGF1. Together, these in vivo findings establish a critical role for SAFB1 in development, growth regulation, and reproduction.