Haploinsufficiency of the essential gene Rps12 causes defects in erythropoiesis and hematopoietic stem cell maintenance.
Haploinsufficiency of the essential gene Rps12 causes defects in erythropoiesis and hematopoietic stem cell maintenance.
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DOI：
10.7554/elife.69322
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发表时间：
2023-06-05
期刊：
影响因子：
7.7
通讯作者：
Baker NE
中科院分区：
文献类型：
--
作者：
Folgado-Marco V;Ames K;Chuen J;Gritsman K;Baker NE
核糖体蛋白（Rp）基因单倍型不足可导致Diamond-Blackfan贫血（DBA），其特征在于红细胞生成缺陷和骨骼缺陷。一些小鼠Rp突变重演DBA表型，虽然其他缺乏红细胞生成或骨骼缺陷。我们产生了一个条件性敲除小鼠部分删除Rps 12。纯合Rps 12缺失导致胚胎死亡。遗传Rps 12 KO/+基因型的小鼠具有生长和形态缺陷、全血细胞减少和红细胞生成受损。骨髓（BM）中造血干细胞（HSC）和祖细胞的显著减少与竞争性和非竞争性BM移植后血液系统重建能力的降低有关。Rps 12 KO/+使HSC失去静止，经历ERK和MTOR激活，并增加HSC和祖细胞中的整体翻译。出生后使用Tal 1-Cre-ERT在造血细胞中杂合缺失Rps 12也导致全血细胞减少症和HSC数量减少。然而，出生后Cre-ERT诱导导致造血干细胞和祖细胞翻译减少，表明这是造血细胞中Rps 12单倍不足的最直接后果。因此，除了红细胞生成之外，RpS 12在HSC功能中具有强烈的需求。
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.