Lamin B1 is required for mouse development and nuclear integrity

Abstract

Lamins are key structural components of the nuclear lamina, an intermediate filament meshwork that lies beneath the inner nuclear membrane. Lamins play a role in nuclear architecture, DNA replication, and gene expression. Mutations affecting A-type lamins have been associated with a variety of human diseases, including muscular dystrophy, cardiomyopathy, lipodystrophy, and progeria, but mutations in B-type lamins have never been identified in humans or in experimental animals. To investigate the in vivo function of lamin B1, the major B-type lamin, we generated mice with an insertional mutation in Lmnb1. The mutation resulted in the synthesis of a mutant lamin B1 protein lacking several key functional domains, including a portion of the rod domain, the nuclear localization signal, and the CAAX motif (the carboxylterminal signal for farnesylation). Homozygous Lmnb1 mutant mice survived embryonic development but died at birth with defects in lung and bone. Fibroblasts from mutant embryos grew under standard cell-culture conditions but displayed grossly misshapen nuclei, impaired differentiation, increased polyploidy, and premature senescence. Thus, the lamin B1 mutant mice provide evidence for a broad and nonredundant function of lamin B1 in mammalian development. These mutant mice and cell lines derived from them will be useful models for studying the role of the nuclear lamina in various cellular processes.nuclear envelope ͉ lamins ͉ knockout mice ͉ gene trapping T he nuclear lamina, a protein meshwork that lines the inner nuclear membrane, is critical in fundamental cellular processes, including nuclear organization, chromatin segregation, DNA replication, and gene transcription (1-5). The principal protein components of the lamina are lamins, which are members of the intermediate filament protein family. Like other intermediate filament proteins, lamins possess an aminoterminal head domain and a highly conserved central ␣-rod domain for polymerization and oligomerization (6). Lamins are, however, distinguished from other intermediate filament proteins by a nuclear localization motif. In addition, prelamin A and lamins B1 and B2 contain a carboxyl-terminal CAAX motif that triggers a series of posttranslational modifications (farnesylation, endoproteolytic trimming of the last three amino acid residues, and methylation of the newly exposed farnesylcysteine) (6). Aside from their structural role in the formation of the nuclear lamina, lamins A and C are found in the nucleoplasm adjacent to sites of DNA synthesis and RNA processing, suggesting that these proteins could influence both DNA replication and gene expression (2,7,8).In vertebrates, lamins are classified as A or B type, based on sequence homology, expression pattern, biochemical properties, and localization during mitosis. The A-type lamins, lamins A and C, are synthesized from alternatively spliced transcripts of LMNA and are expressed in most differentiated cells (9). Somatic cells also express two B-type lamins, lamin B1 and lamin B2, which are encode...

The B-type lamin is required for somatic repression of testis-specific gene clusters

“…This hypothesis is supported by the studies that link mutations in mammalian B-type lamins with developmental disorders such as autosomal dominant leukodystrophy, premature cell senescence, and lipodystrophy (27)(28)(29), and by observation of defects suggesting accelerated aging and neuromuscular degeneration in the Drosophila mutant for the B-type lamin LamDm 0 (30). Moreover, even a wider spectrum of similar degenerative tissue-specific diseases has been associated with mutations in the nuclear envelope components interacting with both the B-and the A/C-type lamins, and in the A/C-type lamins themselves (31)(32)(33)(34)(35)(36)(37)(38).…”

Mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses

“…Loss of emerin expression results in X-linked Emery-Dreifuss muscular dystrophy, a specific disorder of muscle development [52,53]. Mutation of the lamin B1 gene, Lmb1, in mice disrupts both skeletal and lung development, leads to nuclear abnormalities, and disrupts the proliferative capacity of primary embryonic fibroblasts [54]. Mutations in the human LMNA gene cause laminopathies that affect at least five distinct developmental pathways, and cells overexpressing a mutant lamin A protein display abnormal exit from the cell cycle [55,56].…”

Eliminating the Synthesis of Mature Lamin A Reduces Disease Phenotypes in Mice Carrying a Hutchinson-Gilford Progeria Syndrome Allele

“…For example, it would be intriguing to determine whether transgenic overexpression of lamins A and C (27) would affect the severity of disease. Similarly, it would be interesting to determine whether a lamin B1 knock-out allele (28) would influence the severity of progeria. Ultimately, these genetic studies could yield clues regarding the functional relevance of different lamin proteins in the pathogenesis of progeria.…”