Haploinsufficiency of the essential gene Rps12 causes defects in erythropoiesis and hematopoietic stem cell maintenance

  1. Virginia folgado-marco
  2. Kristina Ames
  3. Jacky Chuen
  4. Kira Gritsman  Is a corresponding author
  5. Nicholas E Baker  Is a corresponding author
  1. 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.

Data availability

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.

Article and author information

Author details

  1. Virginia folgado-marco

    Department of Genetics, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kristina Ames

    Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jacky Chuen

    Department of Genetics, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kira Gritsman

    Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    kira.gritsman@einsteinmed.org
    Competing interests
    The authors declare that no competing interests exist.
  5. Nicholas E Baker

    Department of Genetics, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    nicholas.baker@einsteinmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4250-3488

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.

Reviewing Editor

  1. Michael Buszczak, University of Texas Southwestern Medical Center, United States

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.

Version history

  1. Received: April 12, 2021
  2. Preprint posted: May 4, 2021 (view preprint)
  3. Accepted: April 26, 2023
  4. Accepted Manuscript published: June 5, 2023 (version 1)
  5. Version of Record published: June 22, 2023 (version 2)

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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  1. Virginia folgado-marco
  2. Kristina Ames
  3. Jacky Chuen
  4. Kira Gritsman
  5. Nicholas E Baker
(2023)
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

Share this article

https://doi.org/10.7554/eLife.69322

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