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Vol. 57, No. 1, 2011
Issue release date: December 2010
Free Access
Gerontology 2011;57:76–84
(DOI:10.1159/000281882)

Nuclear and Chromatin Reorganization during Cell Senescence and Aging – A Mini-Review

Shin D.-M. · Kucia M. · Ratajczak M.Z.
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Ky., USA
email Corresponding Author

Abstract

Genetic material in the nucleus governs mechanisms related to cell proliferation, differentiation, and function. Thus, senescence and aging are directly tied to the change of nuclear function and structure. The most important mechanisms that affect cell senescence are: (i) telomere shortening; (ii) environmental stress-mediated accumulation of DNA mutations, and (iii) the intrinsically encoded biological clock that dictates lifespan events of any particular cell type. Overall, these changes lead to modification of the expression of genes that are responsible for: (i) organization of the nuclear structure; (ii) integrity of transcriptionally inactive heterochromatin, and (iii) epigenetic modification of chromosomes due to DNA methylation and/or histone modifications. These aging-related nuclear alterations do not only affect somatic cells. More importantly, they affect stem cells, which are responsible for proper tissue rejuvenation. In this review, we focus on epigenetic changes in the chromatin structure and their impact on the biology and function of adult cells as they age. We will also address aging-related changes in a compartment of the most primitive pluripotent stem cells that were recently identified by our team and named ‘very small embryonic/epiblast-like stem cells’.


 goto top of outline Key Words

  • Aging
  • Telomeres
  • Heterochromatin
  • Very small embryonic/epiblast-like stem cells

 goto top of outline Abstract

Genetic material in the nucleus governs mechanisms related to cell proliferation, differentiation, and function. Thus, senescence and aging are directly tied to the change of nuclear function and structure. The most important mechanisms that affect cell senescence are: (i) telomere shortening; (ii) environmental stress-mediated accumulation of DNA mutations, and (iii) the intrinsically encoded biological clock that dictates lifespan events of any particular cell type. Overall, these changes lead to modification of the expression of genes that are responsible for: (i) organization of the nuclear structure; (ii) integrity of transcriptionally inactive heterochromatin, and (iii) epigenetic modification of chromosomes due to DNA methylation and/or histone modifications. These aging-related nuclear alterations do not only affect somatic cells. More importantly, they affect stem cells, which are responsible for proper tissue rejuvenation. In this review, we focus on epigenetic changes in the chromatin structure and their impact on the biology and function of adult cells as they age. We will also address aging-related changes in a compartment of the most primitive pluripotent stem cells that were recently identified by our team and named ‘very small embryonic/epiblast-like stem cells’.

Copyright © 2010 S. Karger AG, Basel


 goto top of outline References
  1. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J: Evidence for cardiomocyte renewal in humans. Science 2009;324:98–102.
  2. Oberdoerffer P, Sinclair DA: The role of nuclear architecture in genomic instability and aging. Nat Rev Mol Cell Biol 2007;8:692–702.
  3. Fraga MF, Esteller M: Epigenetics and aging: the targets and the marks. Trends Genet 2007;23:413–418.
  4. Blasco MA: Telomere length, stem cells and aging. Nat Chem Biol 2007;3:640–649.
  5. Collado M, Blasco MA, Serrano M: Cellular senescence in cancer and aging. Cell 2007;130:223–233.
  6. Vijg J: Somatic mutations and aging: a re-evaluation. Mutat Res 2000;447:117–135.
  7. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A: Does oxidative damage to DNA increase with age? Proc Natl Acad Sci USA 2001;98:10469–10474.
  8. Rehen SK, Yung YC, McCreight MP, Kaushal D, Yang AH, Almeida BSV, Kingsbury MA, Cabral KMS, McConnell MJ, Anliker B, Fontanoz M, Chun J: Constitutional aneuploidy in the normal human brain. J Neurosci 2005;25:2176–2180.
  9. Margueron R, Trojer P, Reinberg D: The key to development: Interpreting the histone code? Curr Opin Genet Dev 2005;15:163–176.
  10. Klose RJ, Bird AP: Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006;31:89–97.
  11. Hata K, Okano M, Lei H, Li E: Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 2002;129:1983–1993.
  12. Van Attikum H, Gasser SM: The histone code at DNA breaks: a guide to repair? Nat Rev Mol Cell Biol 2005;6:757–765.
  13. Hennekam RC: Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A 2006;140A:2603–2624.
  14. Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR, Erdos MR, Eriksson M, Goldman AE, Khuon S, Collins FS, Jenuwein T, Goldman RD: Mutant nuclear lamin a leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci USA 2006;103:8703–8708.
  15. Yu C-E, Oshima J, Fu Y-H, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD: Positional cloning of the Werner’s syndrome gene. Science 1996;272:258–262.
  16. Shiloh Y: Ataxia telangiectasia: closer to unraveling the mystery. Eur J Hum Genet 1995;3:116–138.
  17. Gaubatz JW, Cutler RG: Mouse satellite DNA is transcribed in senescent cardiac muscle. J Biol Chem 1990;265:17753–17758.
  18. Bennett-Baker PE, Wilkowski J, Burke DT: Age-associated activation of epigenetically repressed genes in the mouse. Genetics 2003;165:2055–2062.
  19. Millis AJ, Hoyle M, McCue HM, Martini H: Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts. Exp Cell Res 1992;201:373–379.
  20. Imai S, Kitano H: Heterochromatin islands and their dynamic reorganization: a hypothesis for three distinctive features of cellular aging. Exp Gerontol 1998;33:555–570.
  21. Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW: Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003;113:703–716.
  22. Wilson VL, Jones PA: DNA methylation decreases in aging but not in immortal cells. Science 1983;220:1055–1057.
  23. Casillas MA, Lopatina N, Andrews LG, Tollefsbol TO: Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol Cell Biochem 2003;252:33–43.
  24. Guarente L, Picard FI: Calorie restriction – the SIR2 connection. Cell 2005;120:473–482.
  25. Vaquero A, Sternglanz R, Reinberg D: NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. Oncogene 2007;26:5505–5520.
  26. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA: Calorie restriction promotes mammalian cell survival by inducing the sirt1 deacetylase. Science 2004;305:390–392.
  27. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J: Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1i. Cell 2006;127:1109–1122.
  28. Van der Horst A, Burgering BMT: Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 2007;8:440–450.
  29. Russell SJ, Kahn CR: Endocrine regulation of aging. Nat Rev Mol Cell Biol 2007;8:681–691.
  30. Sharpless NE, DePinho RA: How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 2007;8:703–713.
  31. Ratajczak MZ, Zuba-Surma EK, Shin DM, Ratajczak J, Kucia M: Very small embryonic-like stem cells in adult organs and their potential role in rejuvenation of tissues and longevity. Exp Gerontol 2008;43:1009–1017.
  32. Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J, Ratajczak MZ: A population of very small embryonic-like CXCR4+ SSEA-1+ Oct-4+ stem cells identified in adult bone marrow. Leukemia 2006;20:857–869.
  33. Zuba-Surma E, Kucia M, Ratajczak J, Ratajczak MZ: ‘Small stem cells’ in adult tissues: very small embryonic-like stem cells stand up! Cytometry A 2009;75:4–13.
  34. Kucia M, Halasa M, Wysoczynski M, Baskiewicz-Masiuk M, Moldenhawer S, Zuba-Surma E, Czajka R, Wojakowski W, Machalinski B, Ratajczak MZ: Morphological and molecular characterization of novel population of CXCR4+ SSEA-4+ Oct-4+ very small embryonic-like cells purified from human cord blood: preliminary report. Leukemia 2006;21:297–303.
  35. Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Paczkowska E, Ciosek J, Halasa M, Król M, Kazmierski M, Buszman P, Ochala A, Ratajczak J, Machalinski B, Ratajczak MZ: Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. J Am Coll Cardiol 2009;53:1–9.
  36. Paczkowska E, Kucia M, Koziarska D, Halasa M, Safranow K, Masiuk M, Karbicka A, Nowik M, Nowacki P, Ratajczak MZ, Machalinski B: Clinical evidence that very small embryonic-like stem cells are mobilized into peripheral blood in patients after stroke. Stroke 2009;40:1237–1244.
  37. Shin DM, Zuba-Surma EK, Wu W, Ratajczak J, Wysoczynski M, Ratajczak MZ, Kucia M: Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct-4+ very small embryonic-like stem cells. Leukemia 2009;23:2042–2051.
  38. Reik W, Walter J: Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001;2:21–32.
  39. Itier JM, Tremp GL, Leonard JF, Multon MC, Ret G, Schweighoffer F, Tocque B, Bluet- Pajot MT, Cormier V, Dautry F: Imprinted gene in postnatal growth role. Nature 1998;393:125–126.
  40. Font de Mora J, Esteban LM, Burks DJ, Nunez A, Garces C, Garcia-Barrado MJ, Iglesias-Osma MC, Moratinos J, Ward JM, Santos E: Ras-GRF1 signaling is required for normal β-cell development and glucose homeostasis. EMBO J 2003;22:3039–3049.

 goto top of outline Author Contacts

Mariusz Z. Ratajczak, MD, PhD
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville
500 S. Floyd Street, Rm 107, Louisville, KY 40202 (USA)
Tel. +1 502 852 1788, Fax +1 502 852 3032
E-Mail mzrata01@louisville.edu


 goto top of outline Article Information

Received: August 3, 2009
Accepted: November 4, 2009
Published online: February 4, 2010
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 0, Number of References : 40


 goto top of outline Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 57, No. 1, Year 2011 (Cover Date: December 2010)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

For additional information: http://www.karger.com/GER


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Genetic material in the nucleus governs mechanisms related to cell proliferation, differentiation, and function. Thus, senescence and aging are directly tied to the change of nuclear function and structure. The most important mechanisms that affect cell senescence are: (i) telomere shortening; (ii) environmental stress-mediated accumulation of DNA mutations, and (iii) the intrinsically encoded biological clock that dictates lifespan events of any particular cell type. Overall, these changes lead to modification of the expression of genes that are responsible for: (i) organization of the nuclear structure; (ii) integrity of transcriptionally inactive heterochromatin, and (iii) epigenetic modification of chromosomes due to DNA methylation and/or histone modifications. These aging-related nuclear alterations do not only affect somatic cells. More importantly, they affect stem cells, which are responsible for proper tissue rejuvenation. In this review, we focus on epigenetic changes in the chromatin structure and their impact on the biology and function of adult cells as they age. We will also address aging-related changes in a compartment of the most primitive pluripotent stem cells that were recently identified by our team and named ‘very small embryonic/epiblast-like stem cells’.



 goto top of outline Author Contacts

Mariusz Z. Ratajczak, MD, PhD
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville
500 S. Floyd Street, Rm 107, Louisville, KY 40202 (USA)
Tel. +1 502 852 1788, Fax +1 502 852 3032
E-Mail mzrata01@louisville.edu


 goto top of outline Article Information

Received: August 3, 2009
Accepted: November 4, 2009
Published online: February 4, 2010
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 0, Number of References : 40


 goto top of outline Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 57, No. 1, Year 2011 (Cover Date: December 2010)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

For additional information: http://www.karger.com/GER


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J: Evidence for cardiomocyte renewal in humans. Science 2009;324:98–102.
  2. Oberdoerffer P, Sinclair DA: The role of nuclear architecture in genomic instability and aging. Nat Rev Mol Cell Biol 2007;8:692–702.
  3. Fraga MF, Esteller M: Epigenetics and aging: the targets and the marks. Trends Genet 2007;23:413–418.
  4. Blasco MA: Telomere length, stem cells and aging. Nat Chem Biol 2007;3:640–649.
  5. Collado M, Blasco MA, Serrano M: Cellular senescence in cancer and aging. Cell 2007;130:223–233.
  6. Vijg J: Somatic mutations and aging: a re-evaluation. Mutat Res 2000;447:117–135.
  7. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A: Does oxidative damage to DNA increase with age? Proc Natl Acad Sci USA 2001;98:10469–10474.
  8. Rehen SK, Yung YC, McCreight MP, Kaushal D, Yang AH, Almeida BSV, Kingsbury MA, Cabral KMS, McConnell MJ, Anliker B, Fontanoz M, Chun J: Constitutional aneuploidy in the normal human brain. J Neurosci 2005;25:2176–2180.
  9. Margueron R, Trojer P, Reinberg D: The key to development: Interpreting the histone code? Curr Opin Genet Dev 2005;15:163–176.
  10. Klose RJ, Bird AP: Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006;31:89–97.
  11. Hata K, Okano M, Lei H, Li E: Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 2002;129:1983–1993.
  12. Van Attikum H, Gasser SM: The histone code at DNA breaks: a guide to repair? Nat Rev Mol Cell Biol 2005;6:757–765.
  13. Hennekam RC: Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A 2006;140A:2603–2624.
  14. Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR, Erdos MR, Eriksson M, Goldman AE, Khuon S, Collins FS, Jenuwein T, Goldman RD: Mutant nuclear lamin a leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci USA 2006;103:8703–8708.
  15. Yu C-E, Oshima J, Fu Y-H, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD: Positional cloning of the Werner’s syndrome gene. Science 1996;272:258–262.
  16. Shiloh Y: Ataxia telangiectasia: closer to unraveling the mystery. Eur J Hum Genet 1995;3:116–138.
  17. Gaubatz JW, Cutler RG: Mouse satellite DNA is transcribed in senescent cardiac muscle. J Biol Chem 1990;265:17753–17758.
  18. Bennett-Baker PE, Wilkowski J, Burke DT: Age-associated activation of epigenetically repressed genes in the mouse. Genetics 2003;165:2055–2062.
  19. Millis AJ, Hoyle M, McCue HM, Martini H: Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts. Exp Cell Res 1992;201:373–379.
  20. Imai S, Kitano H: Heterochromatin islands and their dynamic reorganization: a hypothesis for three distinctive features of cellular aging. Exp Gerontol 1998;33:555–570.
  21. Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW: Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003;113:703–716.
  22. Wilson VL, Jones PA: DNA methylation decreases in aging but not in immortal cells. Science 1983;220:1055–1057.
  23. Casillas MA, Lopatina N, Andrews LG, Tollefsbol TO: Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol Cell Biochem 2003;252:33–43.
  24. Guarente L, Picard FI: Calorie restriction – the SIR2 connection. Cell 2005;120:473–482.
  25. Vaquero A, Sternglanz R, Reinberg D: NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. Oncogene 2007;26:5505–5520.
  26. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA: Calorie restriction promotes mammalian cell survival by inducing the sirt1 deacetylase. Science 2004;305:390–392.
  27. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J: Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1i. Cell 2006;127:1109–1122.
  28. Van der Horst A, Burgering BMT: Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 2007;8:440–450.
  29. Russell SJ, Kahn CR: Endocrine regulation of aging. Nat Rev Mol Cell Biol 2007;8:681–691.
  30. Sharpless NE, DePinho RA: How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 2007;8:703–713.
  31. Ratajczak MZ, Zuba-Surma EK, Shin DM, Ratajczak J, Kucia M: Very small embryonic-like stem cells in adult organs and their potential role in rejuvenation of tissues and longevity. Exp Gerontol 2008;43:1009–1017.
  32. Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J, Ratajczak MZ: A population of very small embryonic-like CXCR4+ SSEA-1+ Oct-4+ stem cells identified in adult bone marrow. Leukemia 2006;20:857–869.
  33. Zuba-Surma E, Kucia M, Ratajczak J, Ratajczak MZ: ‘Small stem cells’ in adult tissues: very small embryonic-like stem cells stand up! Cytometry A 2009;75:4–13.
  34. Kucia M, Halasa M, Wysoczynski M, Baskiewicz-Masiuk M, Moldenhawer S, Zuba-Surma E, Czajka R, Wojakowski W, Machalinski B, Ratajczak MZ: Morphological and molecular characterization of novel population of CXCR4+ SSEA-4+ Oct-4+ very small embryonic-like cells purified from human cord blood: preliminary report. Leukemia 2006;21:297–303.
  35. Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Paczkowska E, Ciosek J, Halasa M, Król M, Kazmierski M, Buszman P, Ochala A, Ratajczak J, Machalinski B, Ratajczak MZ: Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. J Am Coll Cardiol 2009;53:1–9.
  36. Paczkowska E, Kucia M, Koziarska D, Halasa M, Safranow K, Masiuk M, Karbicka A, Nowik M, Nowacki P, Ratajczak MZ, Machalinski B: Clinical evidence that very small embryonic-like stem cells are mobilized into peripheral blood in patients after stroke. Stroke 2009;40:1237–1244.
  37. Shin DM, Zuba-Surma EK, Wu W, Ratajczak J, Wysoczynski M, Ratajczak MZ, Kucia M: Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct-4+ very small embryonic-like stem cells. Leukemia 2009;23:2042–2051.
  38. Reik W, Walter J: Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001;2:21–32.
  39. Itier JM, Tremp GL, Leonard JF, Multon MC, Ret G, Schweighoffer F, Tocque B, Bluet- Pajot MT, Cormier V, Dautry F: Imprinted gene in postnatal growth role. Nature 1998;393:125–126.
  40. Font de Mora J, Esteban LM, Burks DJ, Nunez A, Garces C, Garcia-Barrado MJ, Iglesias-Osma MC, Moratinos J, Ward JM, Santos E: Ras-GRF1 signaling is required for normal β-cell development and glucose homeostasis. EMBO J 2003;22:3039–3049.