Lamin: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

Gene name - Lamin

Synonyms - Lamin Dm0

Cytological map position - 25F1--25F2

Function - intermediate filament, chromatin associated protein

Keywords - cytoskeleton, chromatin associated proteins

Symbol - Lam

FlyBase ID: FBgn0002525

Genetic map position - 2-[17].

Classification - nuclear lamin

Cellular location - nuclear



NCBI links: Precomputed BLAST | Entrez Gene

Recent literature
Hayashi, D., Tanabe, K., Katsube, H. and Inoue, Y. H. (2016). B-type nuclear lamin and the nuclear pore complex Nup107-160 influences maintenance of the spindle envelope required for cytokinesis in Drosophila male meiosis. Biol Open [Epub ahead of print]. PubMed ID: 27402967
Summary:
In higher eukaryotes, nuclear envelope (NE) disassembly allows chromatin to condense and spindle microtubules to access kinetochores. The nuclear lamina, which strengthens the NE, is composed of a polymer meshwork made of A- and B-type lamins. This study found that the B-type lamin (Lam) is not fully disassembled and continues to localize along the spindle envelope structure during Drosophila male meiosis I, while the A-type lamin (LamC) is completely dispersed throughout the cytoplasm. Among the nuclear pore complex proteins, Nup107 co-localized with Lam during this meiotic division. Surprisingly, Lam depletion resulted in a higher frequency of cytokinesis failure in male meiosis. The similar meiotic phenotype was observed in Nup107-depleted cells. Abnormal localization of Lam was found in the Nup-depleted cells at premeiotic and meiotic stages. The central spindle microtubules became abnormal and recruitment of a contractile ring component to the cleavage sites was disrupted in Lam-depleted cells and Nup107-depleted cells. Therefore, it is speculated that both proteins are required for a reinforcement of the spindle envelope, which supports the formation of central spindle microtubules essential for cytokinesis in Drosophila male meiosis.
Zhang, X., Xu, K., Wei, D., Wu, W., Yang, K. and Yuan, M. (2017). Baculovirus infection induces disruption of the nuclear lamina. Sci Rep 7(1): 7823. PubMed ID: 28798307
Summary:
Baculovirus nucleocapsids egress from the nucleus primarily via budding at the nuclear membrane. The nuclear lamina underlying the nuclear membrane represents a substantial barrier to nuclear egress. Whether the nuclear lamina undergoes disruption during baculovirus infection remains unknown. This study generated clonal cell line, Sf9-L, that stably expresses GFP-tagged Drosophila lamin B. GFP autofluorescence colocalized with immunofluorescent anti-lamin B at the nuclear rim of Sf9-L cells, indicating GFP-lamin B was incorporated into the nuclear lamina. Meanwhile, virus was able to replicate normally in Sf9-L cells. Next, alterations to the nuclear lamina were investigated during baculovirus infection in Sf9-L cells. A portion of GFP-lamin B localized diffusely at the nuclear rim, and some GFP-lamin B was redistributed within the nucleus during the late phase of infection, suggesting the nuclear lamina was partially disrupted. Immunoelectron microscopy revealed associations between GFP-lamin B and the edges of the electron-dense stromal mattes of the virogenic stroma, intranuclear microvesicles, and ODV envelopes and nucleocapsids within the nucleus, indicating the release of some GFP-lamin B from the nuclear lamina. Additionally, GFP-lamin B phosphorylation increased upon infection. Based on these data, baculovirus infection induced lamin B phosphorylation and disruption of the nuclear lamina.
Petrovsky, R. and Grosshans, J. (2018). Expression of lamina proteins Lamin and Kugelkern suppresses stem cell proliferation. Nucleus 9(1): 104-118. PubMed ID: 29210315
Summary:
The nuclear lamina is involved in numerous cellular functions, such as gene expression, nuclear organization, nuclear stability, and cell proliferation. The mechanism underlying the involvement of lamina is often not clear, especially in physiological or developmental contexts. This study investigated the role and activity of farnesylated lamina proteins Lamin (Lam) and Kugelkern (Kuk) in proliferation control of intestinal stem cells (ISCs) in adult Drosophila flies. ISCs mutant for Lam or kuk proliferate, whereas overexpression of Lam or Kuk strongly suppressed proliferation. The anti-proliferative activity is, at least in part, due to suppression of Jak/Stat but not Delta/Notch signaling. Lam expression suppresses Jak/Stat signaling by normalization of about 50% of the Stat target genes in ISCs.
Nazer, E., Dale, R. K., Chinen, M., Radmanesh, B. and Lei, E. P. (2018). Argonaute2 and LaminB modulate gene expression by controlling chromatin topology. PLoS Genet 14(3): e1007276. PubMed ID: 29529026
Summary:
Drosophila Argonaute2 (AGO2) has been shown to regulate expression of certain loci in an RNA interference (RNAi)-independent manner, but its genome-wide function on chromatin remains unknown. This study identified the nuclear scaffolding protein LaminB as a novel interactor of AGO2. When either AGO2 or LaminB are depleted in Kc cells, similar transcription changes are observed genome-wide. In particular, changes in expression occur mainly in active or potentially active chromatin, both inside and outside LaminB-associated domains (LADs). Furthermore, this study identified a somatic target of AGO2 transcriptional repression, no hitter (nht), which is immersed in a LAD located within a repressive topologically-associated domain (TAD). Null mutation but not catalytic inactivation of AGO2 leads to ectopic expression of nht and downstream spermatogenesis genes. Depletion of either AGO2 or LaminB results in reduced looping interactions within the nht TAD as well as ectopic inter-TAD interactions, as detected by 4C-seq analysis. Overall, these findings reveal coordination of AGO2 and LaminB function to dictate genome architecture and thereby regulate gene expression.
Petrovsky, R., Krohne, G. and Grosshans, J. (2018). Overexpression of the lamina proteins Lamin and Kugelkern induces specific ultrastructural alterations in the morphology of the nuclear envelope of intestinal stem cells and enterocytes. Eur J Cell Biol 97(2): 102-113. PubMed ID: 29395481
Summary:
The nuclear envelope has a stereotypic morphology consisting of a flat double layer of the inner and outer nuclear membrane, with interspersed nuclear pores. Underlying and tightly linked to the inner nuclear membrane is the nuclear lamina, a proteinous layer of intermediate filament proteins and associated proteins. Physiological, experimental or pathological alterations in the constitution of the lamina lead to changes in nuclear morphology, such as blebs and lobulations. It has so far remained unclear whether the morphological changes depend on the differentiation state and the specific lamina protein. This study analysed the ultrastructural morphology of the nuclear envelope in intestinal stem cells and differentiated enterocytes in adult Drosophila flies, in which the proteins Lam, Kugelkern or a farnesylated variant of LamC were overexpressed. Surprisingly, distinct morphological features specific for the respective protein were detected. Lam induced envelopes with multiple layers of membrane and lamina, surrounding the whole nucleus whereas farnesylated LamC induced the formation of a thick fibrillary lamina. In contrast, Kugelkern induced single-layered and double-layered intranuclear membrane structures, which are likely be derived from infoldings of the inner nuclear membrane or of the double layer of the envelope.

BIOLOGICAL OVERVIEW

Nuclear lamins belong to the intermediate filament (IF) superfamily of proteins that includes type I and II IFs called keratins (a component of wool fibers), type III IF (such a vimentin, desmin and peripherin), type IV IF (expressed in axons, dendrites and perikarya), and type V IF, proteins making up nuclear lamina (Fuchs, 1994). Drosophila Lamin is one of two nuclear lamins. Lamin is expressed constitutively, in contrast to the second Drosophila lamin, Lamin C, which is developmentally regulated (Riemer, 1995). Lamins are the major structural proteins of the nuclear lamina, a structure that lines the nucleoplasmic surface of the inner nuclear membrane in higher eukaryotic cells. The nuclear lamina is composed of a meshwork of 10 nm filaments that are thought to provide a skeletal support for the nuclear envelope and to mediate the attachment of the nuclear envelope to interphase chromatin. Additional functions of the nuclear lamina may include the proper organization and anchoring of nuclear pore complexes. During mitosis the lamins also play a crucial role in the disassembly and reassembly of the nuclear envelope (Lenz-Bohme, 1997 and references).

Before describing the biological properties of Drosophila Lamin, the general properties of the IF superfamily members will be described. IF proteins are all predicted to share a common secondary structure. All IF proteins have a central alpha-helical domain, the rod, which is flanked by nonhelical head (amino-end) and tail (carboxy-end) domains. The rods of two polypeptide chains intertwine in a coiled-coil fashion. Throughout the alpha-helical sequences are repeats of hydrophobic amino acids, such that the first and fourth repeats of every seven residues are frequently apolar. This provides a hydrophobic seal on the helical surface, enabling the coiling between two IF polypeptides. The IF alpha-helical rod is subdivided by three short nonhelical linker segments, which often contain proline or multiple glycine residues (Fuchs, 1994).

For all IFs, the first step in assembly is the formation of parallel, in-register dimers. Upon assembly, lamin dimers align in a head-to-tail fashion to form linear polymers. Most IF proteins can form functional homodimers. Each 10-nm IF filament is composed of smaller protofibrils. IFs appear to have approximately four protofibrils per unit width. It is thought that the conserved amino ends of IF proteins play an important role in assembly of the 10-Nm filament structure. One role of IF tails may be to control lateral associations at the protofilament and protofibril level, thereby influencing filament diameter. In addition, the IF head might promote lateral associations of protofilaments and protofibrils. It is known that headless lamins cannot form a linear array of dimers typical of tail-less and wild-type lamins, suggesting that the lamin head might function in tetramer elongation. Phosphorylation is known to negatively regulate IF assembly. It is thought that the archetypal IF gene had a laminlike structure (Fuchs, 1994 and references).

Lamin Dm0, the precursor form of Lamin, has an apparent molecular mass of 76 kDa and is rapidly processed proteolytically in the cytoplasm into a form migrating at 74 kDa (Lamin Dm1). Lamin Dm1 is imported into the nucleus, where about 50% is posttranslationally modified into a slower migrating form (75 kD) called Lamin Dm2. In vivo pulse-chase studies indicated that lamins Dm1 and Dm2 are in equilibrium. Treatment of lamins Dm1 and Dm2 with phosphatase results in a single form that comigrates with Lamin Dm1 (Smith, 1987 and Smith, 1989). Lamins Dm1 and Dm2 are present as a random mixture of homo- and heterodimers. It is thought that serine 25 is the Lamin Dm2-specific phosphorylation site (Stuurman, 1995).

Lamin is known to interact directly with highly conserved sequences of DNA. Lamin binds with high affinity to scaffold/matrix-associated regions (M/SARs). These DNA sequences are held responsible for mediating the interaction between the nuclear matrix and chromatin. M/SARs are several hundred base pairs long and contain stretches of AT-rich sequences that are likely to form an open chromatin configuration. Indeed, the binding of M/SARs to lamin polymers involves single-stranded regions. In addition, this binding is saturable and requires the minor groove. Lamin polymers also bind to Drosophila centromeric and telomeric sequences. The polymerized alpha-helical rod domain of Lamin, on its own, provides for specific binding to the fushi tarazu M/SAR (Zhao, 1996). The ftz M/SAR functions as an autonomously replicating sequence (ARS) in the budding yeast S. cerevisiae. This M/SAR is found in a 2.57 kb ftz upstream regulatory element. A 189 base pair minimal fragment has ARS function. However, based on growth rates and mitotic stability, its activity is lower than that of the entire SAR. The addition of flanking sequences, including as little as 100 bp of AT-rich DNA to the left of the minimal sequence, can enhance the replicative ability of the ARS. These results implicate lamins in initiation of DNA replication (Amati, 1990 a and b)

Several proteins are associated with the nuclear lamina, and specifically with Lamin proteins. The interaction of lamins with the inner nuclear membrane may be supported by integral membrane proteins, e.g., the putative lamin receptor p54 (Bailer, 1991) or LAPs, the lamina-associate proteins (Foisner, 1993).

One protein associated with Drosophila Lamin is Otefin. Otefin is the corruption and transliteration of the Hebrew word "otef," meaning envelope. Otefin is a peripheral protein of the inner nuclear membrane in Drosophila. During nuclear assembly in vitro, it is required for the attachment of membrane vesicles to chromatin. Otefin colocalizes with Lamin derivatives in situ and presumably in vivo and is present in all somatic cells examined during the different stages of Drosophila development. Otefin is a phosphoprotein in vivo and is a substrate for in vitro phosphorylation by cdc2 kinase and cyclic AMP-dependent protein kinase. It is suggested that Otefin plays a role in the assembly of the Drosophila nuclear envelope (Ashery-Padan, 1997b).

The fs(1)Ya protein (Ya stands for "young arrest") is an essential, maternally encoded, nuclear lamina protein that is under both developmental and cell cycle control. A strong Ya mutation results in early arrest of embryos. Ya mutant embryos arrest with abnormal nuclear envelopes prior to the first mitotic division. Ya unfertilized eggs contain nuclei of different sizes and condensation states, apparently due to abnormal fusion of the meiotic products immediately after meiosis. Lamin is localized at the periphery of the uncondensed nuclei in these eggs. These results suggest that Ya function is required during and after egg maturation to facilitate proper chromatin condensation, rather than to allow a lamin-containing nuclear envelope to form. Ya might bind to chromatin and organize the chromatin structure in early embryos in a way that permits DNA replication. Whether Ya functions in conjunction with lamin is unknown (Liu, 1995).

A Drosophila Lamin mutant shows a severe phenotype: this includes retardation in development, reduced viability, sterility, and impaired locomotion. Mutant adult flies die within 2 weeks after eclosion. Late stages of oogenesis are rarely detected in mutant ovaries, and the egg chambers present show an abnormal morphology. In heads from homozygous mutant flies, Lamin is significantly decreased in nuclei of the densely packed cell bodies of the central nervous system. Reduced Lamin expression causes an enrichment of nuclear pore complexes in cytoplasmic annulate lamellae and in nuclear envelope clusters. Annulate lamellae are stacked sheets of membranes in the cytoplasm that contain pore complexes in high densities and are often continuous with rough endoplasmic reticulum in several cells, particularly the densely packed somata of the central nervous system. Defective nuclear envelopes are also observed. The lack of full lethality at early developmental stages may be due to maternal transmission from heterozygous mothers. Indeed, Lamin protein is highly enriched inside the oocyte nucleus, which may serve as a storage compartment for lamin required during the early nuclear divisions in the embryo. These data constitute the first genetic proof that lamins are essential for the structural organization of the cell nucleus (Lenz-Bohme, 1997).

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

Large clusters of coexpressed tissue-specific genes are abundant on chromosomes of diverse species. The genes coordinately misexpressed in diverse diseases are also found in similar clusters, suggesting that evolutionarily conserved mechanisms regulate expression of large multigenic regions both in normal development and in its pathological disruptions. Studies on individual loci suggest that silent clusters of coregulated genes are embedded in repressed chromatin domains, often localized to the nuclear periphery. To test this model at the genome-wide scale, transcriptional regulation of large testis-specific gene clusters was studied in somatic tissues of Drosophila. These gene clusters showed a drastic paucity of known expressed transgene insertions, indicating that they indeed are embedded in repressed chromatin. Bioinformatics analysis suggested the major role for the B-type lamin, LamDm(o), in repression of large testis-specific gene clusters, showing that in somatic cells as many as three-quarters of these clusters interact with LamDm(o). Ablation of LamDm(o) by using mutants and RNAi led to detachment of testis-specific clusters from nuclear envelope and to their selective transcriptional up-regulation in somatic cells, thus providing the first direct evidence for involvement of the B-type lamin in tissue-specific gene repression. Finally, it was found that transcriptional activation of the lamina-bound testis-specific gene cluster in male germ line is coupled with its translocation away from the nuclear envelope. These studies, which directly link nuclear architecture with coordinated regulation of tissue-specific genes, advance understanding of the mechanisms underlying both normal cell differentiation and developmental disorders caused by lesions in the B-type lamins and interacting proteins (Shevelyov, 2009).

It was hypothesized that, in addition to the somatic silencing of testis-specific gene clusters, LamDm0 is also required for attachment of these clusters to the nuclear envelope. To test this hypothesis, intranuclear positions of the 60D1 and 22A1 regions was determined in the interphase nuclei of cultured S2 cells in which LamDm0 was ablated by RNAi. Fluorescence in situ hybridization (FISH) combined with immunostaining for LamDm0 confirmed RNAi-induced ablation of LamDm0, and showed approximately 2-fold decrease in frequency of the 60D1 and 22A1 loci bound to lamina. Next, association of the 60D1 gene cluster with nuclear envelope wa analyzed during male germ-line differentiation. The whole-mount testes dissected from the third instar larvae were analyzed for intranuclear localization of the 60D1 region by FISH combined with immunostaining for LamDm0. Morphologically, a group of small cells is located at the end of testis and includes spermatogonia, cyst cells and stem cells, in which the 60D1 locus is silent. In these cells, the 60D1 region is associated with nuclear lamina in 76% of nuclei, similarly to the cultured somatic S2 cells. On the contrary, in spermatocytes (identified by characteristic large nuclei), in which testis-specific genes in the 60D1 region are expressed, this region is found at the nuclear envelope in only 6% of the nuclei. Thus, transcriptional activation of the testis-specific gene cluster in male germ line is coupled to its dissociation from the nuclear envelope. Similarly, detachment from the nuclear lamina has been associated with transcriptional activation of other lamina-bound loci both in Drosophila and in mammals. These observations strongly suggest a model in which gene repression is controlled in a cell type-specific manner through regulated tethering of chromatin to the nuclear lamina. Further dissection of the mechanisms that mediate repression of lamina-bound multigenic regions and control localization of these regions at nuclear envelope will provide new insights into coordinated regulation of tissue-specific genes, thus advancing understanding of cell differentiation both in normal development and in disease (Shevelyov, 2009).

Role of histone deacetylases in gene regulation at nuclear lamina

Theoretical models suggest that gene silencing at the nuclear periphery may involve 'closing' of chromatin by transcriptional repressors, such as histone deacetylases (HDACs). This study provides experimental evidence confirming these predictions. Histone acetylation, chromatin compactness, and gene repression in lamina-interacting multigenic chromatin domains were analyzed in Drosophila S2 cells in which B-type lamin, diverse HDACs, and lamina-associated proteins were downregulated by dsRNA. Lamin depletion resulted in decreased compactness of the repressed multigenic domain associated with its detachment from the lamina and enhanced histone acetylation. The data reveal the major role for HDAC1 in mediating deacetylation, chromatin compaction, and gene silencing in the multigenic domain, and an auxiliary role for HDAC3 that is required for retention of the domain at the lamina. These findings demonstrate the manifold and central involvement of class I HDACs in regulation of lamina-associated genes, illuminating a mechanism by which these enzymes can orchestrate normal and pathological development (Milon, 2012).

This study provides direct experimental evidence for the long-persisting assumptions that HDACs are involved in gene silencing at the nuclear lamina, by identifying Class I enzymes HDAC1 and HDAC3 as the major players in this mechanism. Likewise gene silencing, histone hypoacetylation and chromatin compaction in the multigenic chromatin domain are lamin-dependent. Moreover, HDAC1 was identified as the key factor required for silencing and specifically responsible for histone H4 deacetylation, and the data implicate HDAC3 as an auxiliary factor specifically responsible for localization of the repressed chromatin at the lamina. The 'closed' chromatin configuration of the repressed domain also depends on HDAC1 and thus probably mediates the major repressive action of this enzyme at the nuclear periphery. Published data indicate that the 60D1 cluster interacts with HDAC1, in particular in the Crtp and Pros28.1B regions, supporting direct involvement of this enzyme in histone deacetylation. A model is proposed in which Class I HDACs participate in lamina-dependent gene silencing through diverse pathways: HDAC1, tethered to the lamin scaffold by LEM domain proteins, is involved in deacetylation of histones H3 and H4 and 'closing' of lamina-bound chromatin while HDAC3 contributes to histone H3 deacetylation and retention of the repressed chromatin at the lamina. Interestingly, a recent study showed that HDAC3 is also involved in peripheral localization of the lamina-interacting chromatin in mammals (Zullo, 2012) indicating that this mechanism is conserved between diverse animals (Milon, 2012).

Lamina-associated chromatin domains harbor numerous cell type-specific genes that must be precisely regulated to orchestrate cell differentiation and development. Genetic defects in the lamina components result in severe and currently incurable tissue degenerative disorders known as laminopathies. Identification of the key role of Class I HDACs, and particularly HDAC1, in lamina-associated gene silencing implies that modulation of this enzyme may help to restore gene expression disrupted by nuclear lamina defects, and may be instrumental in establishing new expression patterns in pluripotent cells to guide their differentiation (Milon, 2012).

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).


GENE STRUCTURE

The Drosophila Lamin gene is developmentally regulated, giving rise to a 2.8 kb maternal transcript and a 3.0 kb zygotic transcript. The different transcripts are generated by utilizing different polyadenylation sites. None of the putative lamin polyadenylation signals contains the consensus AAUAA sequence. The choice between the different polyadenylation signals might depend on maternal fators that more efficiently recognize the polyadenylation signal of the 2.8 kb transcript (Osman, 1990 and Gruenbaum, 1988)

Bases in 5' UTR - 147

Exons - 4

Bases in 3' UTR - 710 (maternal) and 921 (zygotic)


PROTEIN STRUCTURE

Amino Acids - 621

Structural Domains

Highly specific features of lamins include a nuclear localization signal, a C-terminal CaaX sequence (where C=cysteine; a=aliphatic amino acid; X=any amino acid) and characteristic phosphorylation sites in the N-terminal head and C-terminal tail domains. The nuclear localization signal is responsible for rapid transport of lamins into the nucleus, thus preventing cytoplasmic assembly. Modification by isoprenylation and carboxymethylation at the CaaX motif targets lamins to the inner nuclear membrane (Lenz-Bohme, 1997 and references).


Lamin: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 16 July 97  

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