title: Cell-extrinsic defective lymphocyte development in Lmna(-/-) mice.
abstract: BACKGROUND
  Mutations in the LMNA gene, which encodes all A-type lamins, result in a variety of human diseases termed laminopathies. Lmna(-/-) mice appear normal at birth but become runted as early as 2 weeks of age and develop multiple tissue defects that mimic some aspects of human laminopathies. Lmna(-/-) mice also display smaller spleens and thymuses. In this study, we investigated whether altered lymphoid organ sizes are correlated with specific defects in lymphocyte development.
  
  
  RESULTS
  Lmna(-/-) mice displayed severe age-dependent defects in T and B cell development which coincided with runting. Lmna(-/-) bone marrow reconstituted normal T and B cell development in irradiated wild-type recipients, driving generation of functional and self-MHC restricted CD4(+) and CD8(+) T cells. Transplantation of Lmna(-/-) neonatal thymus lobes into syngeneic wild-type recipients resulted in good engraftment of thymic tissue and normal thymocyte development.
  
  
  CONCLUSIONS
  Collectively, these data demonstrate that the severe defects in lymphocyte development that characterize Lmna(-/-) mice do not result directly from the loss of A-type lamin function in lymphocytes or thymic stroma. Instead, the immune defects in Lmna(-/-) mice likely reflect indirect damage, perhaps resulting from prolonged stress due to the striated muscle dystrophies that occur in these mice.
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, United States of America.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Hale
authors.forename: Richard L
authors.initials: RL
authors.lastname: Frock
authors.forename: Sara A
authors.initials: SA
authors.lastname: Mamman
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Fink
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D034904:Lamin Type A / Q000172:deficiency* / Q000235:genetics; D008214:Lymphocytes / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009136:Muscular Dystrophies; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology
chemical_list: D034904:Lamin Type A
references.citation: J Immunol. 2009 Apr 1;182(7):4267-74
references.pmid: 19299725
references.citation: Nat Cell Biol. 2008 Apr;10(4):452-9
references.pmid: 18311132
references.citation: J Cell Sci. 1990 Apr;95 ( Pt 4):587-98
references.pmid: 2200797
references.citation: Biochem Cell Biol. 1988 Jan;66(1):40-53
references.pmid: 3370142
references.citation: J Immunol. 2008 Apr 1;180(7):4742-53
references.pmid: 18354198
references.citation: Genes Dev. 2000 Nov 15;14(22):2855-68
references.pmid: 11090133
references.citation: Exp Cell Res. 1990 Jul;189(1):145-7
references.pmid: 2347374
references.citation: Annu Rev Immunol. 2003;21:139-76
references.pmid: 12414722
references.citation: J Clin Invest. 2004 Feb;113(3):357-69
references.pmid: 14755333
references.citation: Nat Rev Immunol. 2008 Sep;8(9):726-36
references.pmid: 19172693
references.citation: Exp Cell Res. 2009 Apr 1;315(6):996-1007
references.pmid: 19272320
references.citation: Histochem Cell Biol. 1997 Jun;107(6):505-17
references.pmid: 9243284
references.citation: Nat Med. 2001 Aug;7(8):913-9
references.pmid: 11479623
references.citation: Histopathology. 1997 Oct;31(4):304-12
references.pmid: 9363444
references.citation: Development. 1989 Feb;105(2):365-78
references.pmid: 2680424
references.citation: J Cell Biol. 1995 Oct;131(1):33-44
references.pmid: 7559784
references.citation: Genes Dev. 2006 Feb 15;20(4):486-500
references.pmid: 16481476
references.citation: Biochem Soc Trans. 2008 Dec;36(Pt 6):1329-34
references.pmid: 19021550
references.citation: Leuk Res. 1990;14(9):815-21
references.pmid: 2232854
references.citation: J Clin Invest. 2004 Feb;113(3):370-8
references.pmid: 14755334
references.citation: EMBO J. 1987 Dec 1;6(12):3795-9
references.pmid: 3501373
references.citation: J Cell Sci. 2004 Mar 1;117(Pt 7):1173-8
references.pmid: 14996939
references.citation: Eur J Immunol. 2006 Oct;36(10):2566-73
references.pmid: 17013987
references.citation: Hum Mol Genet. 2006 Feb 15;15(4):637-51
references.pmid: 16403804
references.citation: Oncogene. 1994 Sep;9(9):2649-53
references.pmid: 8058329
references.citation: J Cell Biol. 1999 Nov 29;147(5):913-20
references.pmid: 10579712