Haploinsufficiency of the essential gene RpS12 causes defects in erythropoiesis and hematopoietic stem cell maintenance

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, which results in homozygous embryonic lethality. Rps12+/- mice have 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. The mutants exhibited loss of HSC quiescence, which was associated with ERK and MTOR activation and increased global translation in HSC and progenitors. Thus, RpS12 has a very strong requirement in maintaining HSC quiescence and function, in addition to erythropoiesis that is affected in DBA patients.