Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects
Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects
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DOI：
10.1182/blood.v99.1.111
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发表时间：
2002-01-01
期刊：
影响因子：
20.3
通讯作者：
Stanley, ER
中科院分区：
文献类型：
--
作者：
Dai, XM;Ryan, GR;Stanley, ER
集落刺激因子1（CSF-1）是单核吞噬细胞产生的主要调节因子，其作用被认为是由c-fms原癌基因编码的CSF-1受体（CSF-1 R）介导的。为了研究CSF-1对CSF-1 R的体内特异性，将小鼠Csf 1 r基因失活。Csf 1（-）/Csf 1 r（-）小鼠的表型与CSF-1缺失型（Csf 1（op）/Csf 1（op））小鼠的表型非常相似，包括骨硬化、造血、组织巨噬细胞和生殖表型。对比：与野生型同窝出生的小鼠相比，Csf 1（op）/Csf 1（op）和Csf 1（-）/Csf 1 r（-）小鼠的脾红细胞爆发形成单位和高增殖潜能集落形成细胞水平显著升高，这与CSF-1在红细胞生成和维持原始造血祖细胞中的负调节作用一致。Csfr（-）/Csf 1 r（-）小鼠的循环CSF-1浓度升高了20倍，这与先前报道的通过CSF-1 R介导的内吞作用和细胞内破坏清除循环CSF-1的结果一致。尽管它们总体上相似，但Csf 1 r（-）/Csf 1 r（-）小鼠的几个表型特征比Csf 1（op）/Csf 1（op）小鼠更严重。结果表明，CSF-1的所有作用都是通过CSF-1 R介导的，但CSF-1 R的微妙作用可能是由其CSF-1非依赖性激活引起的。
The effects of colony-stimulating factor 1 (CSF-1), the primary regulator of mononuclear phagocyte production, are thought to be mediated by the CSF-1 receptor (CSF-1R), encoded by the c-fms proto-oncogene. To investigate the in vivo specificity of CSF-1 for the CSF-1R, the mouse Csf1r gene was inactivated. The phenotype of Csf1(-)/Csf1r(-) mice closely resembled the phenotype of CSF-1-nullizygous (Csf1(op)/Csf1(op)) mice, including the osteopetrotic, hematopoietic, tissue macrophage, and reproductive phenotypes. Compared: with their wildtype littermates, splenic erythroid burst-forming unit and high-proliferative potential colony-forming cell levels in both Csf1(op)/Csf1(op) and Csf1(-)/Csf1r(-) mice were significantly elevated, consistent with a negative regulatory role of CSF-1 in erythropoiesis and the maintenance of primitive hematopoietic progenitor cells. The circulating CSF-1 concentration in Csfr(-)/Csf1r(-) mice was elevated 20-fold, in agreement with the previously reported clearance of circulating CSF-1 by CSF-1R-mediated endocytosis and intracellular destruction Despite their overall similarity, several phenotypic characteristics of the Csf1r(-)/Csf1r(-) mice were more severe than those of the Csf1(op)/Csf1(op) mice. The results indicate that all of the effects of CSF-1 are mediated via the CSF-1R, but that subtle effects of the CSF-1R could result from its CSF-1-independent activation.