Lamin


DEVELOPMENTAL BIOLOGY

Age-associated loss of lamin-B leads to systemic inflammation and gut hyperplasia

Aging of immune organs (see Drosophila as a Model for Human Diseases: Aging and Lifespan), termed as immunosenescence, is suspected to promote systemic inflammation and age-associated disease. The cause of immunosenescence and how it promotes disease, however, has remained unclear. This study reports that the Drosophila fat body, a major immune organ, undergoes immunosenescence and mounts strong systemic inflammation that leads to deregulation of immune deficiency (IMD) signaling in the midgut of old animals. Inflamed old fat bodies secrete circulating peptidoglycan recognition proteins that repress IMD activity in the midgut, thereby promoting gut hyperplasia. Further, fat body immunosenecence is caused by age-associated lamin-B reduction specifically in fat body cells, which then contributes to heterochromatin loss and derepression of genes involved in immune responses. As lamin-associated heterochromatin domains are enriched for genes involved in immune response in both Drosophila and mammalian cells, these findings may provide insights into the cause and consequence of immunosenescence during mammalian aging (Chen, 2014).

By analyzing gene expression changes upon aging in fat bodies and midguts, it was shown that an increase of immune response in the fat body is accompanied by a striking reduction in the midgut. Specifically, it was demonstrate that the age-associated increase in Immune deficiency (IMD) signaling in fat bodies leads to reduction of IMD activity in the midgut, which in turn contributes to midgut hyperplasia. This fat body to midgut effect requires peptidoglycan recognition proteins (PGRPs) secreted from fat body cells and is mediated by both bacteria dependent and independent pathways. Therefore, fat body aging contributes to systemic inflammation, which contributes to the disruption of gut homeostasis. Importantly, it was shown that the age-associated lamin-B loss in fat body cells causes the derepression of a large number of immune responsive genes, thereby resulting in fat body-based systemic inflammation (Chen, 2014).

B-type lamins have long been suggested to have a role in maintaining heterochromatin and gene repression. Consistently, this study's global analyses of fat body depleted of lamin-B revealed a loss of heterochromatin and derepression of a large number of immune responsive genes. This is further supported by ChIP-qPCR analyses of H3K9me3 on specific IMD regulators. Recent studies in different cell types show that tethering genes to nuclear lamins do not always lead to their repression. Deleting B-type lamins or all lamins in mouse ES cells or trophectdoderm cells does not result in derepression of all genes in LADs. In light of these studies, it is suggested that the transcriptional repression function of lamin-B could be gene and cell type dependent. Interestingly, GO analyses revealed a significant enrichment of immune responsive genes in Lamin-associated domains (LADs) in four different mammalian cell types and Drosophila Kc cells. Since the large-scale pattern of LADs is conserved in different cell types in mammals, it is possible that the immune-responsive genes are also enriched in LADs in the fly fat body cells. Supporting this notion, the IKKγ, key, which is one of the two derepressed IMD regulators and was found to exhibit H3K9me3 reduction and gene activation, is localized to LADs in Kc cells. It is speculated that lamin-B might play an evolutionarily conserved role in repressing a subset of inflammatory genes in certain tissues, such as the immune organs, in the absence of infection or injury. Consistently, senescence-associated lamin-B1 loss in mammalian fibroblasts is correlated with senescence-associated secretory phenotype senescence-associated secretory phenotype (SASP). Although the in vivo relevance of fibroblast SASP in chronic inflammation and aging-associated diseases in mammals remains to be established, the findings in Drosophila provide insights and impetus to investigate the role of lamins in immunosenescence and systemic inflammation in mammals (Chen, 2014).

Lamin-B gradually decreases in fat body cells of aging flies, whereas lamin-C amount remains the same. Since it has been recently shown that the assembly of an even and dense nuclear lamina is dependent on the total lamin concentration, the age-associated appearance of lamin-B and lamin-C gaps around the nuclear periphery of fat body cells is likely caused by the drop of the lamin-B level. How aging triggers lamin-B loss is unknown, but it appears to be posttranscriptional, because lamin-B transcripts in fat bodies remain unchanged upon aging. Interestingly, among the tissues examined, no changes of lamin-B and lamin-C proteins were found in cells in the heart tube, oenocytes, or gut epithelia in old flies. Therefore, the age-associated lamin-B loss does not occur in all cell types in vivo. A systematic survey to establish the cell/tissue types that undergo age-associated reduction of lamins in both flies and mammals should provide clues to the cause of loss. Deciphering how advanced age leads to lamin loss should open the door to further investigate the cellular mechanism that contributes to chronic systemic inflammation and how it in turn promotes age-associated diseases in humans (Chen, 2014).

Old Drosophila gut is known to exhibit increased microbial load, which would cause increased stress response and activation of tissue repair, thereby leading to midgut hyperplasia. Systemic inflammation caused by lamin-B loss in fat body leads to repression of local midgut IMD signaling. The upregulation of targets of IMD in the aged whole gut has been recently reported, while a downregulation of target genes was observed in the current analyses of the midgut. However, the previous study found a similar upregulation of the genes when performing RNA-seq of the whole gut (Chen, 2014).

These studies reveal an involvement of bacteria in the repression of midgut IMD signaling by the PGRPs secreted from the fat body. How PGRPs from the fat body repress midgut IMD is still unknown. One possibility is that the body cavity bacteria contribute to the maintenance of midgut IMD activity, and the increased circulating PGRPs limit these bacteria. The circulating PGRPs may also reduce midgut IMD activity indirectly by affecting other tissues. The evidence suggests that lamin-B loss could also contribute to midgut hyperplasia independent of the IMD pathway. While it will be important to further address these possibilities, the findings have revealed a fat body mediated inflammatory pathway that can lead to reduced migut IMD, increased gut microbial accumulation, and midgut hyperplasia upon aging (Chen, 2014).

Interestingly, microbiota changes also occur in aging human intestine and have been linked to altered intestinal inflammatory states and diseases. Although, much effort has been devoted to understand how local changes in aging mammalian intestines affect gut microbial community, the cause remains unclear. The findings in Drosophila reveal the importance of understanding the impact of immunosenescence and systemic inflammation on gut microbial homeostasis. Indeed, if increased circulating inflammatory cytokines perturb the ability of local intestine epithelium and the gut-associated lymphoid tissue to maintain a balanced microbial community, the unfavorable microbiota in the old intestine would cause chronic stress response and tissue repair, thereby leading to uncontrolled cell growth as observed in age-associated cancers (Chen, 2014).

Effects of Mutation or Deletion

A Drosophila Lamin mutant is described resulting from a P element insertion into the first intron of the Lamin gene. Homozygous mutant animals showed a severe phenotype including retardation in development, reduced viability, sterility, and impaired locomotion. Reduced Lamin expression causes an enrichment of nuclear pore complexes in cytoplasmic annulate lamellae and in nuclear envelope clusters. In several cells, particularly the densely packed somata of the central nervous system, defective nuclear envelopes are also observed. All aspects of the mutant phenotype are rescued upon P element-mediated germline transformation with a Lamin transgene. These data constitute the first genetic proof that lamins are essential for the structural organization of the cell nucleus (Lenz-Bohme, 1997).

The functions of Klarsicht and nuclear lamin in developmentally regulated nuclear migrations of photoreceptor cells in the Drosophila eye

The Klarsicht (Klar) protein is a crucial factor in the regulation of bidirectional transport of lipid droplets. Lipid droplets in early embryos move bidirectionally along microtubules, and the balance of plus- and minus-end travel distances changes twice over a 2-h period, resulting in switches in the direction of net transport. In the absence of Klar, travel distances, travel velocities, and stall forces are greatly reduced, for both plus- and minus-end travel. Without Klar the motors for plus- and minus-end motion are active indiscriminately, engaging in a tug-of-war. Thus, Klar seems to be central for understanding how the activity of opposite-polarity motors is coordinated during bidirectional transport. In this system, Klar controls the minus-end motor cytoplasmic dynein and an as yet unknown plus-end motor (Patterson, 2004; Guo, 2005 and references therein).

In its role in photoreceptor nuclear migration, Klarsicht is required for connecting the microtubule organizing center (MTOC) to the nucleus. In addition, in a genetic screen for klarsicht-interacting genes, Lam Dm0, which encodes nuclear lamin, was found. Like Klarsicht, lamin is required for photoreceptor nuclear migration and for nuclear attachment to the MTOC. Moreover, perinuclear localization of Klarsicht requires lamin. It is proposed that nuclear migration requires linkage of the MTOC to the nucleus through an interaction between microtubules, Klarsicht, and lamin (Patterson, 2004).

Nuclear migration in the developing eye is critical for shaping each individual cell and thus for normal morphology of the entire compound eye. The Drosophila compound eye develops within the larval eye imaginal disc, an epithelial monolayer. Within the eye disc, the morphogenetic furrow marks the initiation of eye assembly. Rows of identical facets, or ommatidia, assemble posterior to the furrow, starting with the eight photoreceptors (R-cells), followed by the lens-secreting cone cells, and finally the pigment cells. Anterior to the furrow, cells are undifferentiated and their nuclei are positioned randomly within the monolayer. The nuclei dive basally within the furrow and posterior to the furrow, migrate apically as they are recruited into ommatidia (Patterson, 2004 and references therein).

Two Drosophila genes, klarsicht (previously known as marbles) and Glued, are essential for the apical migration of nuclei in differentiating R-cells (Fischer-Vize, 1994; Fan, 1997). Glued encodes the large subunit of dynactin, a protein complex that regulates the minus-end-directed microtubule motor dynein. The requirement for dynactin suggests that R-cell nuclear migration is a dynein- and microtubule-dependent process. Consistent with this idea, two other Drosophila genes, Bicaudal-D< and Lis1, both of which may regulate dynein, are implicated in R-cell nuclear migration, although their mutant phenotypes are weak compared with klarsicht and Glued. Lis-1, a WD40 repeat protein, is the homolog of the human disease gene Lissencephaly-1. Lissencephaly, or smooth brain, is a disorder resulting from defects in neuronal migrations essential for normal human brain development. Neuronal migration requires nuclear migration, and the involvement of Lis-1 in Drosophila R-cell nuclear migration suggests that the two processes may be in part analogous. It is now clear that a connection between the MTOC and the nucleus is necessary for nuclear migration and that this connection is mediated by Klar and nuclear lamin. In addition to suggesting a specific role for Klar in nuclear migration, the results propose a general mechanistic explanation for the cytoplasmic effects of nuclear lamin, including human laminopathies (Patterson, 2004).

To understand the role of Klar in R-cell nuclear migration, Klar subcellular localization and the position of the MTOC was investigated in klar mutant eye discs. In addition, genetics was used to identify nuclear lamin, which functions in the same pathway with Klar. Klar was found to be perinuclear and associated with microtubules apical to the nucleus. In addition, in klar and Lam mutant discs, MTOCs form normally in R-cells, but are often not associated with the nucleus as they are in wild-type eyes. Finally, Lam+ was found to be required for Klar localization to the nuclear membrane. These observations, taken together with previous results, suggest a model for the function of Klar in nuclear migration where Klar, held in the nuclear envelope by nuclear lamin, links the nucleus to the MTOC (Patterson, 2004).

The interaction between Klar and lamin may be indirect, but it is likely to be specific, rather than a generalized failure of nuclear envelope assembly in Lam mutants. Although most R-cell nuclei fail to migrate apically even in weak, viable Lam mutants, >90% of nuclear envelopes are intact even in stronger, lethal Lam mutants (Patterson, 2004 and references therein).

It is proposed that one or more proteins may form a bridge between the KASH domain of Klar, present in the outer nuclear membrane, and nuclear lamin, in the inner nuclear envelope. The observation that in addition to its perinuclear localization, Klar is cytoplasmic (on apical microtubules) supports the idea that Klar is in the outer, as opposed to the inner, nuclear membrane. Similarly, C. elegans Anc-1 is present in the cytoplasm as well as the nuclear membrane, and a model has been proposed where the Anc-1 KASH domain is held in the outer nuclear membrane by an inner nuclear membrane protein, Unc-84. Although nuclear lamin has not been shown directly to be required for Anc-1 nuclear membrane localization, nuclear envelope localization of Unc-84 requires lamin. For Syne-1, the vertebrate homolog of Anc-1, experiments where the detergent digitonin was used to allow antibody access to the outer but not the inner nuclear membrane provide direct evidence that the KASH domain is in the outer nuclear membrane (Zhen, 2002). There is, however, some conflicting data (Patterson, 2004 and references therein).

It is speculated that the N-terminal portion of Klar is linked to microtubules by dynein. At present, it is not possible to test for colocalization of Klar and dynein because there are no available reagents that allow detection of dynein or dynactin in the eye disc. Nevertheless, there is much evidence to support an essential role for dynein in R-cell nuclear migration and Klar function. Dynactin, a regulator of dynein, is essential for R-cell nuclear migration in the eye; mutants in the p150 dynactin subunit (Glued) have a phenotype similar to that of klar mutants in the eye disc. In addition, dynein linkage could explain why Klar is localized to microtubules only apical to the nucleus; Klar that escapes the hold of the nuclear envelope, still attached to dynein, could walk along microtubules to the MTOC. Finally, Klar has been implicated as a regulator of dynein in Drosophila embryos. In addition to its role in R-cell nuclear migration, Klar is required for developmentally regulated migration of lipid storage vesicles during embryogenesis. Lipid droplets at the center of the cellular blastoderm embryo normally migrate cortically during gastrulation. In embryos from klar mutant mothers, the lipid droplets fail to migrate. A variety of data support a model where dynein transports the lipid droplets along microtubules, whose minus ends are at the cell periphery. The results of biophysical experiments has led to a model where Klar may attach the appropriate types of motor to lipid droplets, control the number of actively engaged motors on a droplet, or coordinate the activities of kinesins and dyneins bound simultaneously to the same droplet. Notably, dynein is required for nuclear attachment to centrosomes (the MTOCs) during mitosis in the Drosophila embryo. Klar, however, is not essential for this process (Patterson, 2004 and references therein).

The observation that the MTOC is normally apical to the R-cell nuclei, at the leading edge of nuclear movement, suggests that a force pulls on the MTOC from above. It is speculated that the mechanism for this force could be analogous to the means by which the nucleus of budding yeast are pulled into the bud neck before cell division. One pathway for migration of the nucleus into the bud neck involves dynein, anchored at the cell cortex to which the nucleus is moving. Cortically tethered dynein 'reels in' the nucleus by walking along microtubules whose plus ends are at the cortex, toward the MTOC, which is anchored to the nucleus. In support of this idea, microtubule plus-ends are present apically in R-cells, and dynactin is essential for R-cell nuclear migration (Patterson, 2004 and references therein).

Whether a force emanating from the apical membrane pulling on the MTOC would drive nuclear migration or serve as an anchor after the nucleus has migrated depends on where the MTOC initially forms. The gamma-tubulin antibody detects MTOCs only apically in differentiating cells. Transiently basal MTOCs associated with nuclei that are about to rise could have escaped detection. However, if the MTOC does form apically, then the force that drives nuclear migration would come from below the nucleus, that is, dynein, linked to the nuclear membrane by Klar and lamin, walking on microtubules up toward the MTOC (Patterson, 2004).

The model proposed whereby Klar forms a bridge between nuclear lamin in the inner nuclear membrane and cytoplasmic microtubules provides a general framework for explaining how nuclear lamin affects cytoplasmic events. Drosophila Lam mutations result in D/V polarity defects in eggs, and tracheal branching defects in embryos. Moreover, a variety of human diseases are the result of mutations in the LMNA gene, which encodes lamin A. The Drosophila Lam Dm0 gene encodes type B lamin, whereas the Drosophila LamC gene encodes lamin C, which is most similar to human lamin A. The A/C- and B-type lamins are similar proteins, with some different structural features, and some expression pattern differences. LMNA-associated human diseases affect the heart, skeletal muscles, and the nervous system (Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, cardiomyopathy, and Charcot-Marie-Tooth disorder), and metabolism (Dunnigan-type lipodystrophy). The two main hypotheses as to how nuclear lamin defects can result in these disease phenotypes are that the mutations either result in nuclear envelope fragility or result in changes in gene expression. An alternative hypothesis is that the inner nuclear envelope interacts with the cytoplasm through proteins like Klar or Anc-1/Syne-1, which connect the inner nuclear envelope to the microtubule, or actin cytoskeletons, respectively (Patterson, 2004 and references therein).


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lamin Dm0: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 26 December 2016 

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