Abstract

The gene LMNA encodes the proteins lamins A and C and is implicated in nine different laminopathies — inherited diseases that are linked to premature ageing. Recent evidence has demonstrated that lamins A and C have essential functions in protecting cells from physical damage, as well as in maintaining the function of transcription factors required for the differentiation of adult stem cells. Thus, the degenerative nature of laminopathies is explained because these lamins are essential for maintenance of somatic tissues in adulthood.

Introduction

The intermediate-filament supergene family makes cytoskeletal fibres that provide some of the most resilient structures in metazoan cells. Lamins are type V intermediate-filament proteins and the evolutionary progenitors of the intermediate-filament supergene family. Lamins can be categorized into two sub-families: A-type, which are expressed in most differentiated somatic cells; and B-type, which are expressed in nearly all cells and are essential for cell viability. Recent reports reveal that mutations in A-type lamins, in addition to causing several other diseases, promote premature ageing syndromes termed 'progerias'. Individuals suffering from progerias age about eight times faster than normal and exhibit a wide range of degenerative pathologies, mainly affecting mesenchymal tissues, and generally die from complications of atherosclerosis in their teens. Over a decade ago, the term 'guardian of the genome' was proposed for p53, due to its critical role in regulating apoptosis in cancerous cells. In this review, we discuss the case for describing A-type lamins as guardians of the soma.

Lamins

Intermediate-filament proteins form 10–13-nm filaments in the cytoplasm and nucleus. Lamins are the intermediate-filament family members that are the principle components of the nuclear lamina. They are fairly typical of intermediate-filament proteins, but possess important unique features. They are organized around a central -helical rod comprising three coiled–coil domains separated by flexible linker regions and globular head and tail domains (Fig. 1). The coiled–coil domains are organized around heptad repeats, and the lamins contain an extra 42 residues (six heptads) within coil 1b, when compared with vertebrate cytoplasmic intermediate-filament proteins^{1, 2}. In addition, the tail domain of the lamins harbours a nuclear-localization signal³ and, in most cases, a carboxy-terminal CaaX box, which is a target for isoprenylation and carboxymethylation^{4, 5, 6}. These motifs ensure that lamins enter the nucleus and are located at the inner nuclear membrane (INM). Lamins form obligate parallel coiled-coil dimers, which assemble end-to-end to eventually form filaments 10–13 nm in diameter. In frog oocytes, these filaments line the nucleoplasmic face of the INM, where they form a twodimensional lattice interconnecting nuclear pores⁷. The B-type lamins (lamins B₁, B₂ and B₃) are the initial building blocks of the lamina⁸ and at least one B-type lamin must be expressed in a cell to ensure its viability⁹. A-type lamins (A, A10, C and C₂), all alternatively spliced products of the LMNA gene, are probably built into this structure once it has formed⁸. Although A-type lamins have essential roles in maintaining lamina stability (see below), they also seem to have additional roles in regulating transcription factors¹⁰.

Figure 1: Generalized structure of cytoplasmic intermediate-filament proteins compared to lamins.

Intermediate-filament proteins have a conserved domain structure consisting of a variable globular head domain, a central -helical coiled-coil dimerization domain consisting of four coiled coils, based on heptad repeats, interrupted by flexible linker domains and a variable globular tail domain. The coiled-coil domains are termed 1A, 1B, 2A and 2B, respectively. The linker domains are non-helical. The major differences between lamins and vertebrate cytoplasmic intermediate filaments are that: first, the head domains are very short (about 33 amino acids); second, there is a six-heptad extension of coil 1B; and third, the globular tail domain is usually characterized by possession of a nuclear localization signal sequence and a site for carboxyl methylation, farnesylation and proteolytic cleavage (CaaX).

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The lamina as a tensegrity element

The lamina has been described as a 'tensegrity element', which resists forces of deformation and protects chromatin from physical damage¹¹. This hypothesis is supported by a number of investigations. For example, in cell-free extracts of Xenopus laevis oocytes, either physical or functional depletion of lamins leads to the assembly of very small and fragile nuclei^{12, 13, 14, 15}. Similarly, RNA interference knock-down of C-lam in Caenorhabditis elegans leads to abnormally shaped nuclei that constantly alter their morphology¹⁶. In mouse spermatocytes, nuclei are hook shaped rather than ovoid or spherical and these cells express a germ-line-specific lamin, lamin B₃. When lamin B₃ is expressed ectopically in somatic cells, their nuclei adopt a hook-shaped morphology¹⁷. Finally, expression of a dominant lamin B¹ mutant lacking four fifths of the rod domain causes massive deformation of the nuclear envelope in somatic cells¹⁸. Thus, lamins determine the size, shape and strength of the nuclear envelope and therefore possess the key features of a tensegrity element¹¹. However, the properties of this tensegrity element are probably determined not only by the properties of individual lamins but also by the way that they interact with components of the cytoskeleton.

Recently, a novel family of spectrin-repeat proteins has been described, some members of which are integral proteins of the INM, and others may specifically localize to the outer nuclear membrane. Variously termed nesprins¹⁹, NUANCE²⁰ or synes²¹, these proteins are characterized by the giant size of some alternatively spliced variants (they can have relative molecular masses in excess of 800,000). They possess multiple clustered spectrin repeats throughout the core of the protein, amino-terminal calponin homology domains and a conserved C-terminal singlepass membrane domain. NUANCE binds to actin and its distribution is influenced by the actin cytoskeleton²⁰. In vitro, nesprin 1 — a relatively ocus small nesprin isoform — binds to lamins A and C and to emerin, a type 2 integral membrane protein of the INM²². Its localisation at the INM is dependent on the expression of lamins A and C²³. Nesprins also self associate¹⁹. In addition, emerin directly binds to lamins A/C in vitro and is localized to the INM by a complex of these two proteins^{24, 25}; furthermore, it is also an actin-binding protein²⁶. Thus, lamins A and C can assemble a complex of proteins at the nuclear envelope that have characteristics of cytoskeleton linker proteins²⁷ and potentially link the actin cytoskeleton to the lamina. One model proposes that integral proteins of the INM that bind to lamins A and C interact, either directly or indirectly through proteins in the perinuclear space, with larger nesprin isoforms in the outer nuclear membrane, which in turn bind to cytoskeletal elements. This would mean that when cells express A-type lamins at the point of their differentiation they gain contacts between the lamina and the cytoskeleton.

Given these connections, the tensile properties of the lamina would radiate through the cytoskeleton to the plasma membrane (Fig. 2), generating a mechanotransduction signalling capability in the cell that links the extracellular matrix to the inside of the nucleus²⁸. There is now direct evidence to support this hypothesis. Fibroblasts from Lmna^-/- mice were subjected to mechanical strain, and nuclear deformation and strain-induced signalling simultaneously measured²⁹. Nuclei of fibroblasts from Lmna^-/- mice have notably greater deformation than fibroblasts from Lmna^+/+ littermates, with a resultant decreased viability when subjected to mechanical strain. In addition, NF-B signalling is attenuated in response to either mechanical or cytokine stimulation²⁹. In a complementary study, a bespoke biomechanical device was used to investigate how fibroblasts from the same Lmna^-/- mice resist forces of compression³⁰. The device was capable of simultaneously measuring forces of decompression generated by single cells subjected to compression, while observing how the cells and their nuclei were deformed. Nuclei of fibroblasts from Lmna^-/- mice are notably less able to resist compression compared with nuclei of fibroblasts from Lmna^+/+ mice. In addition, the nuclei of Lmna^-/- mice exhibit isotropic deformation when compressed, whereas Lmna^+/+ mice exhibit anisotropic deformation. This finding implies that nuclei of cells lacking A-type lamins no longer respond to the polarity of the cell and that this lack of response occurrs because all elements of the cytoskeleton are disorganized around the nuclear envelope³⁰. Thus, in mesenchymal cells at least, mechano-induced signalling is propagated by linking the lamina to the cytoskeleton.

Figure 2: Model of the lamina connected to the actin cytoskeleton.

Model of the lamina as a tensegrity structure in which lamin filaments (bars) form a cage-like structure reminiscent of a geodesic dome. The cage is connected to the actin cytoskeleton (long wavy filaments) by nesprins (blue elements) and emerin (red spots), both of which are anchored to the lamina. These connections constrain the shape of the lamina to the polarity of the cell.

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Lamins as regulators of transcription

A number of reports link lamins to transcription and post-transcriptional processing. In Xenopus laevis oocytes, the germ-line specific lamin Liii associates with RNA polymerase II (RNA pol II) and when it is prevented from forming filaments using dominant-negative lamin mutants, RNA pol II activity is inhibited³¹. In somatic cells, lamin B₁ is reported to bind to the POU domain repressor protein Oct-1, which regulates the expression of collagenase genes³². In addition, LAP2, an integral protein of the INM, together with B-type lamins, forms functional complexes with the transcription factors germ-cell-less (GCL) and DP to repress E2F³³. Thus, B-type lamins seem to have negative and positive influences on transcription.

A-type lamins also have roles in RNA metabolism. A-type lamins are distributed throughout the nuclear interior and associate not only with the lamina but also with a range of nuclear bodies. This implies that they are involved in transcription and RNA processing^{34, 35, 36}. In addition, A-type lamins associate with specific transcription factors and at least one of those associations is functional³⁷. A-type lamins are been reported to associate with retinoblastoma protein (Rb)³⁷, sterol response element binding protein 1 (SREPB1)³⁸ and MOK2 (ref. 39), whereas emerin binds to GCL⁴⁰. The C-terminal region of lamins A and C also interacts with DNA⁴¹.

The function of lamin-A– or lamin-C–Rb interactions is now becoming clear. In fibroblasts, lamin A/C and the nucleoskeleton protein LAP2 form a complex with Rb that tethers unphosphorylated forms of the protein within the nucleus⁴². It had previously been shown that tethering of Rb in the nucleus is necessary for its function, and mutant forms of Rb that cannot be tethered promote cancer⁴³. Importantly, these mutants do not interact with lamin-A– or lamin-C–LAP2⁴². Direct evidence for the role of lamins A and C in Rb function has now been reported. In cells from Lmna^-/- mice, Rb is depleted and targeted for destruction by the proteosome¹⁰. Moreover, the fibroblasts exhibit growth and size characteristics typical of fibroblasts from Rb^-/- mice. Thus, the purpose of the lamin-A– or lamin-C–Rb interaction seems to be to prevent targeting of Rb for destruction by the proteosome, thereby regulating cell growth and division (Fig. 3).

Figure 3: Lamin-A–LAP2 complexes are required for Rb function.

A complex of lamin A/C (green) and LAP2 (blue) tethers Rb (red) and thereby prevents its destruction by the proteosome (yellow). In the presence of lamin A/C and LAP2 and the absence of Rb phosphorylation, E2F activity is inhibited and cells remain in G1. When lamin-A/C–LAP2 function is disrupted, Rb is targeted for destruction by the proteosome, thereby de-repressing E2F and allowing cell-cycle progression.

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The laminopathies: Human diseases caused by mutations in LMNA raise new questions

In the early 1990s, human geneticists set out to identify the gene responsible for X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) using a positional cloning approach. They identified a new gene encoding an integral membrane protein they named 'emerin'⁴⁴. They named the protein after Alan Emery, who along with Fritz Dreifuss first described the clinical condition with contractures of the elbows, achilles tendons and posterior neck, slow progressive muscle wasting and cardiomyopathy with atrioventricular conduction block⁴⁵. Subsequently, emerin was shown to localize to the nuclear envelope^{46, 47} and to interact with A-type lamins^{25, 48}. Hence, this was the first human disease identified that was related to an INM protein.

A condition identical to X-EDMD is inherited in an autosomaldominant manner (AD-EDMD). Using positional cloning, another group showed that AD-EDMD is caused by mutations in LMNA⁴⁹. Subsequently, mutations in LMNA were found to cause related autosomal- dominant striated muscle diseases with predominant cardiomyopathy and little-to-no skeletal muscle involvement⁵⁰ or cardiomypathy with a limb-girdle distribution of skeletal muscle involvement⁵¹. Before these discoveries, the structural organization of the lamin-A/C-coding portion of LMNA had been determined⁵². Most mutations in LMNA causing these striated muscle diseases were found to lead to small deletions or amino-acid substitutions throughout lamins A and C, with rare mutations causing haploinsufficiency^{49, 53}.

Dunnigan-type familial partial lipodystrophy (FPLD), or lipoatrophic diabetes, is an autosomal-dominantly inherited disorder characterised by loss of fat from the extremities, excess fat in the face, neck and trunk and insulin resistance⁵⁴. In many aspects, FPLD mimics the metabolic syndrome, which occurs in aging individuals in developed regions of the world and is characterized by abdominal obesity, elevated serum lipids, high blood pressure, insulin resistance, a proinflammatory state and a prothrombotic state⁵⁵. The responsible gene for FPLD was linked to chromosome 1q21–1q22 in 1998 (ref. 56), a chromosomal region to which LMNA had been mapped previously⁵⁷. Subsequently, researchers using a candidate gene approach⁵⁸, and others using positional cloning^{59, 60}, showed that mutations in LMNA cause FPLD. About 90% of mutations are missense mutations localized to exon 8. The amino-acid substitutions alter the charge of a solvent-exposed surface in an immunoglobulin fold in the tail of lamins A and C^{61, 62}. In contrast, amino-acid substitutions in the same region of the molecules that cause striated muscle disease lead to an overall disruption of three-dimensional fold structure. Hence, mutations that cause FPLD lead to subtle changes in lamin A/C molecular structure, whereas mutations causing striated muscle disease result in more dramatic structural alterations. FPLD-causing A-type lamin mutants may function in a dominantly interfering manner, as Lmna^-/- mice do not develop partial lipodystrophy⁶³.

More recent research has shown that mutations in A-type lamins not only cause disorders of striated muscle and adipose but a complicated and perplexing expanding array of diseases. Some homozygous mutations in LMNA cause an autosomal-recessive axonal peripheral neuropathy in humans, and Lmna^-/- mice have pathologically similar peripheral nerve abnormalities⁶⁴. Homozygous mutations in LMNA also cause mandibuloacral dysplasia (MAD), a rare disorder characterized by postnatal growth retardation, skull and facial anomalies, skeletal malformations, mottled skin pigmentation, partial lipodystrophy and signs of premature aging⁶⁵. MAD is also caused by mutations in the ZMPSTE24 protease involved in the processing of pre-lamin A to lamin A, and Zmpste24^-/- mice have phenotypic similarities to humans with MAD^{66, 67, 68}. Recently, heterozygous mutations in both LMNA and ZMPSTE24 have been associated with restrictive dermopathy, also know as 'tight-skin contracture syndrome', another rare disorder mainly characterized by intra-uterine growth retardation, tight and rigid skin with erosions, facial abnormalities, bone-mineralization defects and early neonatal lethality⁶⁹. Autosomalrecessive mutations in LMNA also cause a syndromatic condition with generalized fat loss, insulin-resistant diabetes mellitus, disseminated raised skin lesions, fatty liver and cardiomyopathy⁷⁰.

Perhaps the most dramatic phenotype caused by mutations in LMNA is progeria. Hutchinson-Gildford progeria syndrome (HGPS) is a rare autosomal-dominant condition with growth retardation, abnormal facial development, loss of subcutaneous fat and premature atherosclerosis leading to death in the second decade of life⁷¹. In 2003, two groups^{72, 73} reported a de novo dominant mutation in exon 11 of LMNA in subjects with HGPS. This mutation leads to the creation of an abnormal RNA splice-donor site in exon 11 that results in expression of a truncated pre-lamin A protein with 50 amino acids deleted from its C terminus. This mutation is found in the majority of subjects with HGPS, but other LMNA mutations may be the cause in some subjects^{72, 73, 74}. 'Knock-in' mice with an RNA-splicing mutation, different than the one in human subjects with HGPS, also develop signs of progeria⁷⁵. Mutations in LMNA have also been reported in subjects with atypical premature aging disorders not meeting the diagnostic criteria for HGPS or other specific syndromes^{76, 77}.

That a broad spectrum of disease phenotypes arises from mutations in A-type lamins has raised new questions about their functions. It suggests that these proteins have different roles in different somatic cells. Some mutants, such as those causing progerias, affect multiple cell types. Others mutants, such as those causing EDMD or FPLD, seem to exert effects in a relatively cell type-specific way. The efforts of many cell biologists are now focused on deciphering the cell-specific functions of A-type lamins and determining how mutations cause the range of so-called laminopathies.

The 'structural' and 'gene expression' hypotheses to explain laminopathies

Two working hypotheses have been proposed to explain how laminopathies arise. The 'structural' hypothesis proposes that mutations in A-type lamins or emerin give rise to a weakened nuclear envelope, which is predisposed to damage. In striated muscle particularly, damage to the nucleus is thought to promote myocyte death and cause replacement with fatty and fibrotic tissue^{8, 25, 78}. The 'gene expression' hypothesis proposes that, as A-type lamins are important regulators of gene expression, mutations in these proteins will alter their interactions with various gene regulatory proteins and thereby promote disease in different tissues^{78, 79, 80}. There is now evidence to support each hypothesis, with a consensus emerging that structural weakness and altered gene expression both contribute to pathogenesis.

The case for the structural hypothesis

Studies of fibroblasts from Lmna^-/- mice show that an absence of A-type lamins results in a structurally compromised nuclear envelope that is susceptible to stress-induced damage leading to loss of cell viability^{29, 30}. However, although Lmna^-/- mice do exhibit a phenotype similar to human EDMD^{25, 81}, human diseases caused by mutations in LMNA, including EDMD, do not arise from null genotypes. Nevertheless, there is evidence that mutant A-type lamins promote structural weakness. When lamin A or lamin C mutants are expressed in model cell lines, they often fail to associate appropriately with the nuclear envelope and form aggregates in the nucleoplasm^{82, 83}. Moreover, these mutant lamins can promote structural abnormalities in the nuclear envelope that are commonly observed in fibroblasts from human subjects with laminopathies^{72, 73, 65, 84, 85, 86, 87}. It seems that this structural weakness does translate into physical damage. Ultrastructural investigations of skeletal muscle from subjects with ADEDMD and X-EDMD^{88, 89} and cardiac muscle from Lmna^-/- mice⁸¹ both reveal widespread breakage of nuclear envelopes and leakage of chromatin into the cytoplasm. This damage correlates with cell death. Consistent with these findings, nuclear envelope proteins of fibroblasts from subjects with EDMD exhibit notably increased solubility properties compared with those of normal individuals⁹⁰. Thus, weakness of the nuclear envelope seems to promote cell death. One interesting and unresolved issue is the absence of mutations in LMNA and emerin in about half of subjects with a clinical diagnosis of EDMD⁵³. If the tensegrity model is correct, new candidate genes could include cytoskeleton linker proteins, such as the nesprins or components of the cytoskeleton.

The case for the gene expression hypothesis

Clear evidence is now available for the potential involvement of Rb in laminopathies. Rb is not only involved in cell proliferation but its activity is also required for the differentiation of mesenchymal cells, including skeletal muscle⁹¹ and adipocytes⁹². It is now clear that loss of expression of lamins A and C impairs Rb function and leads to a loss of growth control¹⁰. Expression of lamin A mutants that cause AD-EDMD in C2C12 myoblasts inhibits their differentiation and promotes apoptotic cell death⁹³. These findings correlate with a recent report showing that growth of early-passage fibroblasts from individuals with HGPS is characterized by rapid proliferation but high rates of apoptosis⁸⁵. Therefore, loss of Rb function could be responsible for these phenotypes. Indeed, as an independent investigation has confirmed that the expression of lamin A mutants causing AD-EDMD in C2C12 myoblasts does prevent their differentiation by disrupting LAP2–Rb complexes leading to loss of expression of Rb isoforms⁹⁴. One problem with these findings is that they imply that skeletal muscle differentiation should fail at an early stage in the development of Lmna^-/- mice. However, the mice actually develop normally but experience muscle fibre degeneration after birth²⁵. Because C2C12 myoblasts are derived from satellite cells, they better represent a model for regeneration rather than development. Therefore, we propose that the presence of A-type lamin mutants in adult stem cells may compromise their ability to regenerate some tissues, such as striated muscle, because certain differentiation programmes require Rb function. In the most severe examples, laminopathies may arise because certain cells are susceptible to degeneration through fragility of the nuclear envelope, whilst at the same time adult stem cells may be unable to regenerate damaged tissues through a loss of Rb function.

SREBP1, which has a critical role in adipocyte differentiation, interacts with lamin A in vitro³⁸. Mutations that cause FPLD but not other laminopathies decrease the efficiency of lamin-A–SREBP1 interactions. Therefore, FPLD may be promoted by impairment of SREBP1 function through loss of binding to lamin A. To validate this hypothesis, a more detailed investigation of how lamin A influences SREBP1 activity is required.

A-type lamins as guardians of the soma

We have highlighted two essential functions of A-type lamins and the nuclear lamina. First, they have a role as a load-bearing structure at the centre of the cell, which resists compression and is required for the propagation of stress-induced signalling pathways. Second, lamin complexes have a role in regulating transcriptional repressors and, in particular, lamin A has a role in maintaining Rb function. Loss of A-type lamin function compromises both pathways and leads to degeneration and possibly a lack of normal regeneration of a variety of tissues and, in some cases, premature death. Thus, A-type lamins seem to be essential for survival to old age and should be considered guardians of the soma.

Acknowledgements

C.J.H. is supported by grants from the Association for International Cancer Research, the Muscular Dystrophy Campaign and the Wellcome Trust. H.J.W. is supported by the National Institutes of Health, the Muscular Dystrophy Association and the American Diabetes Association.

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