Haploinsufficiency of the essential gene Rps12 causes defects in erythropoiesis and hematopoietic stem cell maintenance
- Albert Einstein College of Medicine, United States
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 Rps12+/- 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. Rps12+/- mutants 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.
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There are no large-scale datasets associated with this paper. All data generated or analyzed during this study are included in the manuscript and supporting files.
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Funding
National Institute of General Medical Sciences (R01GM104213)
- Nicholas E Baker
National Institute of Diabetes and Digestive and Kidney Diseases (R56DK130895)
- Kira Gritsman
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK130895)
- Kira Gritsman
National Institutes of Health (F32HL146119)
- Kristina Ames
National Institutes of Health (2K12GH102779)
- Kristina Ames
Albert Einstein College of Medicine Human Genetics Program (n/a)
- Nicholas E Baker
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved Institutional Animal Care and Use Committee (IACUC) protocols of the Albert Einstein College of Medicine (Protocol #20181206). All procedures were performed under isoflurane anesthesia to minimize animal suffering.
Copyright
© 2023, folgado-marco et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Haploinsufficiency of the essential gene Rps12 causes defects in erythropoiesis and hematopoietic stem cell maintenance
eLife 12:e69322.
https://doi.org/10.7554/eLife.69322
