PDF(Pubmed)
Abstract：
Ribosomal protein (Rp) gene haploinsufficiency can result in Diamond-Blackfan Anemia (DBA), characterized by defective erythropoiesis and skeletal defects. Some mouse Rp mutations recapitulate DBA phenotypes, although others lack erythropoietic or skeletal defects. We generated a conditional knockout mouse to partially delete Rps12. Homozygous Rps12 deletion resulted in embryonic lethality. Mice inheriting the Rps12KO/+ genotype had growth and morphological defects, pancytopenia, and impaired erythropoiesis. A striking reduction in hematopoietic stem cells (HSCs) and progenitors in the bone marrow (BM) was associated with decreased ability to repopulate the blood system after competitive and non-competitive BM transplantation. Rps12KO/+ lost HSC quiescence, experienced ERK and MTOR activation, and increased global translation in HSC and progenitors. Post-natal heterozygous deletion of Rps12 in hematopoietic cells using Tal1-Cre-ERT also resulted in pancytopenia with decreased HSC numbers. However, post-natal Cre-ERT induction led to reduced translation in HSCs and progenitors, suggesting that this is the most direct consequence of Rps12 haploinsufficiency in hematopoietic cells. Thus, RpS12 has a strong requirement in HSC function, in addition to erythropoiesis.
摘要：
核糖体蛋白（Rp）基因单倍体不足可导致Diamond-Blackfan贫血（DBA），以红细胞生成缺陷和骨骼缺陷为特征。一些小鼠Rp突变概括了DBA表型，尽管其他人缺乏红细胞生成或骨骼缺陷。我们生成了一个条件敲除小鼠来部分删除Rps12。纯合Rps12缺失导致胚胎致死。遗传Rps12+/-基因型的小鼠有生长和形态缺陷，全血细胞减少和红细胞生成受损。骨髓中造血干细胞（HSC）和祖细胞（BM）的显着减少与竞争性和非竞争性BM移植后重新填充血液系统的能力降低有关。Rps12+/-突变体失去了HSC静止，在HSC和祖细胞中经历了ERK和MTOR激活并增加了整体翻译。使用Tal1-Cre-ERT在造血细胞中Rps12的出生后杂合子缺失也导致全血细胞减少，HSC数量减少。然而,出生后Cre-ERT诱导导致HSC和祖细胞翻译减少，这表明这是造血细胞中Rps12单倍体不足的最直接后果。因此，RpS12对HSC功能有很强的要求，除了红细胞生成。
