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Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation

Nature Genetics volume 39, pages 99–105 (2007)Cite this article

An Author Correction to this article was published on 30 April 2020

Abstract

Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1–5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans6 and in mice7,8,9. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.

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Figure 1: Cdkn1a deletion prolongs lifespan and improves maintenance of high-turnover organs in aging mice with dysfunctional telomeres.
Figure 2: Impaired maintenance and function of stem and progenitor cells in aged mice with dysfunctional telomeres.
Figure 3: Cdkn1a deletion does not rescue telomere function or DNA damage signal induction in intestinal crypts of aging iG4 mice.
Figure 4: Deletion of Cdkn1a rescues cell cycle arrest in intestinal progenitor cells and improves repopulation capacity and self-renewal of HSCs from mice with dysfunctional telomeres.
Figure 5: Cdkn1a deletion leaves apoptotic responses intact and does not increase chromosomal instability and carcinogenesis in mice with dysfunctional telomeres.

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Acknowledgements

We thank P. Leder (Department of Genetics, Harvard Medical School) for providing Cdkn1a knockout mice. We thank R. Greenberg and N. Bardeesy for critical discussion and M. Ballmaier (Cell Sorting Core Facility, Hannover Medical School) for cell sorting. K.L.R. is supported by the Deutsche Forschungsgemeinschaft (Heisenberg Professorship: Ru 745/8-1, Ru745 4-1 and KFO119) and the Deutsche Krebshilfe e.V. (10-2236-Ru 2) as well as the Roggenbuck Foundation, the Wilhelm Sander Foundation and the Fritz Thyssen Foundation. H.W.L. was supported by grants from the 21C Frontier Functional Human Genome Project (FG05-22-02) and the BRC Frontier (M103KV010018-05K2201-01830).

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Author notes

  1. Aaheli Roy Choudhury and Zhenyu Ju: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany

    Aaheli Roy Choudhury, Zhenyu Ju, Meta W Djojosubroto, Andrea Schienke, Andre Lechel, Sonja Schaetzlein, Hong Jiang, Anna Stepczynska & K Lenhard Rudolph

  2. Department of Mucosal Immunity, Helmholtz Centre for Infection Research, Braunschweig, 38124, Germany

    Anna Stepczynska & Jan Buer

  3. Institute for Aging and Health, University of Newcastle Upon Tyne, Newcastle, NE46BE, UK

    Chunfang Wang & Thomas von Zglinicki

  4. Institute of Medical Microbiology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany

    Jan Buer

  5. College of Science, Yonsei University, Seoul, 120-749, Korea

    Han-Woong Lee

  6. Department of Hematology and Oncology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany

    Arnold Ganser

  7. Institute of Pathology, University Hospital, Im Neuenheimer Feld 220/221, Heidelberg, 69120, Germany

    Peter Schirmacher

  8. Laboratory of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, 108-8693, Japan

    Hiromitsu Nakauchi

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Contributions

A.R.C., Z.J., A.L., S.S., A. Stepczynska, H.J., C.W., J.B., Tv.Z., A.G., P.S. and H.N. performed phenotype assessment of aging mice; M.W.D., A. Schienke and H.W.L. generated mouse crosses; A.R.C., Z.J., P.S. and H.N. contributed to writing the paper and K.L.R. designed the studies and wrote the paper.

Corresponding author

Correspondence to K Lenhard Rudolph.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

p21 deletion does not rescue critical telomere shortening in iG4mice. (PDF 17 kb)

Supplementary Fig. 2

The reduced lifespan of telomere dysfunctional mice is not associated with impaired organ maintenance at a young age. (PDF 56 kb)

Supplementary Fig. 3

The reduction in function and maintenance of hematopoietic and intestinal stem and progenitor cells in telomere dysfunctional mice is age dependent. (PDF 47 kb)

Supplementary Fig. 4

Absence of widespread accumulation of SA-bGal-positive cells in different organs of aged iG4 mice. (PDF 108 kb)

Supplementary Fig. 5

p21-independent apoptosis in aging telomere-dysfunctional mice. (PDF 86 kb)

Supplementary Table 1

The prevalence and severity of colonic crypt dysplasia for individual mice analyzed at a histological level in 12- to 15-month-old mice. (PDF 22 kb)

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Choudhury, A., Ju, Z., Djojosubroto, M. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39, 99–105 (2007). https://doi.org/10.1038/ng1937

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