Abstract
BackgroundLamin A (LMNA) is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350) and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670). Cells from progeria patients exhibit cell cycle defects in both interphase and mitosis. Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1) activity, leading to aberrant cell cycle control in interphase, but how mitosis is affected by LMNA is not well understood.ResultsWe examined the cell cycle and structural phenotypes of cells from mice with the Lmna allele, Disheveled hair and ears (LmnaDhe). We found that dermal fibroblasts from heterozygous LmnaDhe (LmnaDhe/+) mice exhibit many phenotypes of human laminopathy cells. These include severe perturbations to the nuclear shape and lamina, increased DNA damage, and slow growth rates due to mitotic delay. Interestingly, LmnaDhe/+ fibroblasts also had reduced levels of hypophosphorylated RB1 and the non-SMC condensin II-subunit D3 (NCAP-D3), a mitosis specific centromere condensin subunit that depends on RB1 activity. Mitotic check point control by mitotic arrest deficient-like 1 (MAD2L1) also was perturbed in LmnaDhe /+ cells. LmnaDhe /+ fibroblasts were consistently aneuploid and had higher levels of micronuclei and anaphase bridges than normal fibroblasts, consistent with chromosome segregation defects.ConclusionsThese data indicate that RB1 may be a key regulator of cellular phenotype in laminopathy-related cells, and suggest that the effects of LMNA on RB1 include both interphase and mitotic cell cycle control.
Highlights
The nuclear lamina is a network of Type V intermediate filament proteins that lie primarily beneath the inner nuclear membrane
We examined features of the cell cycle using a newly described Lmna mouse model, Disheveled hair and ears (LmnaDhe), which exhibits a subset of phenotypes of Hutchinson-Gilford progeria syndrome (HGPS) and other non-muscular dystrophy laminopathies, including epidermal dysplasia, craniofacial abnormalities, and markedly thinned hypodermal fat layers [5,6,7,19,29]
We found that dermal fibroblasts from heterozygous LmnaDhe mice had nuclear morphology defects and increased DNA damage, as well as mitotic defects, including aneuploidy, lagging chromosomes and anaphase bridges
Summary
The nuclear lamina is a network of Type V intermediate filament proteins that lie primarily beneath the inner nuclear membrane. It is composed of both A-type (A, AD10, C and C2) and B-type (B1 and B2) lamins. The nuclear lamina participates in cell cycle control, DNA replication, gene transcription, genome three-dimensional (3-D) architecture and stabilization of the nucleus in the cytoplasm [1,2,3,4,5,6,7]. Lamin A (LMNA) is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350) and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670). Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1) activity, leading to aberrant cell cycle control in interphase, but how mitosis is affected by LMNA is not well understood
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