Progressive Lymphopenia Receptor-Deficient Mice Results in Profound Homeostatic Proliferation in Lamin B Reduced Lymphocyte Longevity

Content Provider	Semantic Scholar
Author	Metcalf, Donald Starr, Robyn Hilton, Douglas J. Baldwin Goradia, Ankita Collinge, Janelle E. Benjamin, Thaidigsmann Verhagen, Anne M. Graaf, Carolyn A. De
Copyright Year	2011
Abstract	The lamin B receptor (LBR) is a highly unusual inner nuclear membrane protein with multiple functions. Reduced levels are associated with decreased neutrophil lobularity, whereas complete absence of LBR results in severe skeletal dysplasia and in utero/ perinatal lethality. We describe a mouse pedigree, Lym3, with normal bone marrow and thymic development but profound and progressive lymphopenia particularly within the T cell compartment. This defect arises from a point mutation within the Lbr gene with only trace mutant protein detectable in homozygotes, albeit sufficient for normal development. Reduced T cell homeostatic proliferative potential and life span in vivo were found to contribute to lymphopenia. To investigate the role of LBR in gene silencing in hematopoietic cells, we examined gene expression in wild-type and mutant lymph node CD8 T cells and bone marrow neutrophils. Although LBR deficiency had a very mild impact on gene expression overall, for common genes differentially expressed in both LBR-deficient CD8 T cells and neutrophils, gene upregulation prevailed, supporting a role for LBR in their suppression. In summary, this study demonstrates that LBR deficiency affects not only nuclear architecture but also proliferation, cell viability, and gene expression of hematopoietic cells. T he nuclear envelope comprises the outer and inner membranes , separated by luminal space, and is traversed by nuclear pore complexes. The inner nuclear membrane is lined with a scaffolding structure known as the lamina, which engages the nucleoplasm. The lamina is made up of filamentous proteins called lamins and several lamin-interacting inner nuclear membrane proteins, including the lamin B receptor (LBR). Although the structural role of the lamina in regulating many nuclear functions, including mitosis and meiosis, has long been recognized , there is increasing evidence that the tethering of hetero-chromatin to the nuclear periphery and interaction of the nuclear lamina with epigenetic modifiers and transcription factors is important for transcriptional repression (1–5). Key studies in Dro-sophila and humans have demonstrated low gene expression is correlated with lamina-associated domains (6, 7). In humans, these domains have also been shown to have a lower gene density than non-nuclear lamina tethered regions. The LBR is an inner nuclear membrane protein with dual modality (8–11). It has an N-terminal region, comprising two glob-ular domains, including a Tudor-like DNA binding domain, joined by a linker region, which protrudes into the nucleoplasm where it engages proteins of the nuclear lamina, including lamin B1/B2, heterochromatin protein 1 (HP1), heterochromatic methyl binding …
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://www.jimmunol.org/content/jimmunol/early/2011/11/20/jimmunol.1100942.full.pdf?with-ds=yes
Alternate Webpage(s)	http://www.jimmunol.org/content/jimmunol/188/1/122.full.pdf?with-ds=yes
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article