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Cell-Extrinsic Defective Lymphocyte Development in Lmna-/- Mice

Authors
Journal
PLoS ONE
1932-6203
Publisher
Public Library of Science
Publication Date
Volume
5
Issue
4
Identifiers
DOI: 10.1371/journal.pone.0010127
Keywords
  • Research Article
  • Immunology
  • Developmental Biology/Cell Differentiation
  • Genetics And Genomics/Disease Models
  • Genetics And Genomics/Nuclear Structure And Function
Disciplines
  • Medicine

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. Principal Findings 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.

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