Abstract
BackgroundMutations 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.ConclusionsCollectively, 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.
Highlights
Nuclear lamins are intermediate filament proteins and have roles in various nuclear processes, including DNA replication, chromatin organization, and gene transcription [1,2,3,4]
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
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
Summary
Nuclear lamins are intermediate filament proteins and have roles in various nuclear processes, including DNA replication, chromatin organization, and gene transcription [1,2,3,4]. LMNA, encodes the A-type nuclear lamins, which produce the predominant A-type lamin proteins A and C. Lmna-/- mice are characterized by a variety of tissue-specific defects consistent with those observed in human laminopathies, but display growth defects as early as 2 weeks of age, reduced thymus and spleen size, defective spermatogenesis, and death by 6–8 weeks of age [6,7]. 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. We investigated whether altered lymphoid organ sizes are correlated with specific defects in lymphocyte development
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