ABSTRACT
Emerin and LEM2 are ubiquitous inner nuclear membrane proteins conserved from humans to Caenorhabditis elegans. Loss of human emerin causes Emery-Dreifuss muscular dystrophy (EDMD). To test the roles of emerin and LEM2 in somatic cells, we used null alleles of both genes to generate C. elegans animals that were either hypomorphic (LEM-2-null and heterozygous for Ce-emerin) or null for both proteins. Single-null and hypomorphic animals were viable and fertile. Double-null animals used the maternal pool of Ce-emerin to develop to the larval L2 stage, then arrested. Nondividing somatic cell nuclei appeared normal, whereas dividing cells had abnormal nuclear envelope and chromatin organization and severe defects in postembryonic cell divisions, including the mesodermal lineage. Life span was unaffected by loss of Ce-emerin alone but was significantly reduced in LEM-2-null animals, and double-null animals had an even shorter life span. In addition to striated muscle defects, double-null animals and LEM-2-null animals showed unexpected defects in smooth muscle activity. These findings implicate human LEM2 mutations as a potential cause of EDMD and further suggest human LEM2 mutations might cause distinct disorders of greater severity, since C. elegans lacking only LEM-2 had significantly reduced life span and smooth muscle activity.
Subject(s)
Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/growth & development , Membrane Proteins/physiology , Mitosis/physiology , Muscle, Smooth/physiology , Muscle, Striated/physiology , Nuclear Proteins/physiology , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Cell Cycle Proteins , Cell Proliferation , Chromatin/metabolism , Chromatin/ultrastructure , Gene Deletion , Gene Expression Regulation, Developmental , Humans , Longevity/genetics , Membrane Proteins/genetics , Mesoderm/growth & development , Mesoderm/metabolism , Mitosis/genetics , Muscle Contraction/genetics , Muscle Contraction/physiology , Muscle, Smooth/metabolism , Muscle, Striated/metabolism , Muscular Dystrophy, Emery-Dreifuss/genetics , Mutation , Nuclear Envelope/metabolism , Nuclear Envelope/ultrastructure , Nuclear Proteins/genetics , Sarcomeres/metabolism , Sarcomeres/physiology , Subcutaneous Tissue/growth & development , Subcutaneous Tissue/metabolismABSTRACT
Mutations in lamins cause premature aging syndromes in humans, including the Hutchinson-Gilford Progeria Syndrome (HGPS) and Atypical Werner Syndrome. It has been shown that HGPS cells in culture undergo age-dependent progressive changes in nuclear architecture. However, it is unknown whether similar changes in nuclear architecture occur during the normal aging process. We have observed that major changes of nuclear architecture accompany Caenorhabditis elegans aging. We found that the nuclear architecture in most nonneuronal cell types undergoes progressive and stochastic age-dependent alterations, such as changes of nuclear shape and loss of peripheral heterochromatin. Furthermore, we show that the rate of these alterations is influenced by the insulin/IGF-1 like signaling pathway and that reducing the level of lamin and lamin-associated LEM domain proteins leads to shortening of lifespan. Our work not only provides evidence for changes of nuclear architecture during the normal aging process of a multicellular organism, but also suggests that HGPS is likely a result of acceleration of the normal aging process. Because the nucleus is vital for many cellular functions, our studies raise the possibility that the nucleus is a prominent focal point for regulating aging.
