Functions and dysfunctions of the nuclear lamin Ig-fold domain in nuclear assembly, growth, and Emery–Dreifuss muscular dystrophy

Shumaker, Dale K.; Lopez‐Soler, Reynold I.; Adam, Stephen A.; Herrmann, Harald; Moir, Robert D.; Spann, Timothy P.; Goldman, Robert D.

doi:10.1073/pnas.0507612102

Cited by 49 publications

(67 citation statements)

References 54 publications

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“…Tailless human lamin C formed 15-30 nm filaments instead of paracrystals. Taken together, these and other data [24,25,30] [31]. The Igfold motif in the lamin tail domain was sufficient to inhibit lamin polymerization and nuclear assembly in vitro [31].…”

Section: From Dimers To Filamentsmentioning

confidence: 77%

Nuclear lamins: key regulators of nuclear structure and activities

Prokocimer¹,

Davidovich²,

Nissim-Rafinia³

et al. 2009

Journal of Cellular and Molecular Medicine

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Section: From Dimers To Filamentsmentioning

confidence: 77%

Nuclear lamins: key regulators of nuclear structure and activities

Prokocimer¹,

Davidovich²,

Nissim-Rafinia³

et al. 2009

Journal of Cellular and Molecular Medicine

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“…Several studies have suggested that the head and tail domains are involved in lamin assembly (Herrmann and Foisner, 2003; Isobe et al, 2007;Sasse et al, 1998;Shumaker et al, 2005;Stuurman et al, 1998).…”

Section: Discussion the Function Of The N-terminal Domain Of A-type Lmentioning

confidence: 99%

“…Structural studies implicate the head domain in lamina assembly (Herrmann and Foisner, 2003;Isobe et al, 2007;Sasse et al, 1998;Shumaker et al, 2005;Stuurman et al, 1996). Lamins dimerize through the rod domain and form head-to-tail interactions to generate filaments (Sasse et al, 1998;Stuurman et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

The role ofDrosophilaLamin C in muscle function and gene expression

et al. 2010

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SUMMARYThe inner side of the nuclear envelope (NE) is lined with lamins, a meshwork of intermediate filaments that provides structural support for the nucleus and plays roles in many nuclear processes. Lamins, classified as A-or B-types on the basis of biochemical properties, have a conserved globular head, central rod and C-terminal domain that includes an Ig-fold structural motif. In humans, mutations in A-type lamins give rise to diseases that exhibit tissue-specific defects, such as Emery-Dreifuss muscular dystrophy. Drosophila is being used as a model to determine tissue-specific functions of A-type lamins in development, with implications for understanding human disease mechanisms. The GAL4-UAS system was used to express wild-type and mutant forms of Lamin C (the presumed Drosophila A-type lamin), in an otherwise wild-type background. Larval muscle-specific expression of wild type Drosophila Lamin C caused no overt phenotype. By contrast, larval muscle-specific expression of a truncated form of Lamin C lacking the N-terminal head (Lamin C N) caused muscle defects and semi-lethality, with adult 'escapers' possessing malformed legs. The leg defects were due to a lack of larval muscle function and alterations in hormoneregulated gene expression. The consequences of Lamin C association at a gene were tested directly by targeting a Lamin C DNAbinding domain fusion protein upstream of a reporter gene. Association of Lamin C correlated with localization of the reporter gene at the nuclear periphery and gene repression. These data demonstrate connections among the Drosophila A-type lamin, hormone-induced gene expression and muscle function. DEVELOPMENT 3068 lethality when expressed in larval muscle but not in other tissues (Schulze et al., 2009). By contrast, alterations in the rod domain cause abnormal lamin aggregation within the nucleus but not lethality. Collectively, our studies support a role for the N-terminal head and C-terminal globular domain in larval muscle function.To better understand the role of the N-terminal head domain, we generated transgenic flies expressing a mutant form of Lamin C lacking the first 42 amino acids (Lamin C N) (Schulze et al., 2009). This mutant form localizes to the NE and causes semilethality when expressed in muscle but not in non-muscle tissues (Schulze et al., 2009). Here, we demonstrate that lethality is associated with larval body wall muscle defects that include nuclear and cytoplasmic abnormalities. 'Adult escapers' expressing Lamin C N have leg defects that are consistent with a loss of muscle function and disruptions in ecdysone hormone signaling.Collectively, these studies demonstrate a role for the N-terminal head domain of Lamin C in muscle function and gene expression. MATERIALS AND METHODS Drosophila stocks and genetic analysesDrosophila stocks were raised at room temperature on standard sucrose and cornmeal medium (Shaffer et al., 1994). Generation of transgenic stocks expressing wild type and Lamin C N was previously reported (Schulze et al., 2005;Schulze ...

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“…However, other studies have shown that fragments of XLB3 that inhibit lamin polymerization block NE assembly at the early membrane fusion events, suggesting that lamin assembly is required early in the process of NE formation (17,18). Surprisingly, little is known about the physical state of the XLB3 that is stored in the egg for nuclear assembly during early embryogenesis.…”

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confidence: 94%

Regulation of Nuclear Lamin Polymerization by Importin α

Adam

Sengupta

Goldman

2008

Journal of Biological Chemistry

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Nuclear lamins are integral components of the nuclear envelope and are important for the regulation of many aspects of nuclear function, including gene transcription and DNA replication. During interphase, the lamins form an intranuclear intermediate filament network that must be disassembled and reassembled when cells divide. Little is known about factors regulating this assembly/disassembly cycle. Using in vitro nuclear assembly and lamin assembly assays, we have identified a role for the nuclear transport factor importin ␣ in the regulation of lamin assembly. Exogenous importin ␣ inhibited nuclear lamin assembly in Xenopus interphase egg nuclear assembly assays. Fractionation of the egg extract used for nuclear assembly identified a high molecular weight complex containing the major egg lamin, XLB3, importin ␣, and importin ␤. This complex could be dissociated by RanGTP or a competing nuclear localization sequence, indicating that lamin assembly is Ran-and importin ␣-dependent in the egg extract. We show that the addition of importin ␣ to purified lamin B3 prevents the assembly of lamins in solution. Lamin assembly assays show that importin ␣ prevents the self-association of lamins required to assemble lamin filaments into the typical paracrystals formed in vitro. These results suggest a role for importin ␣ in regulating lamin assembly and possibly modulating the interactions of lamins with lamin-binding proteins.The nuclear envelope (NE) 3 segregates the cytoplasm from the nucleus of eukaryotic cells and regulates macromolecular traffic between these two compartments (1). The NE is an asymmetric organelle composed of a double bilayer membrane and two major protein complexes, the nuclear pore complexes (NPCs) and the nuclear lamina. NPCs punctuate the membranes at points of membrane fusion, forming the channels through which regulated macromolecular traffic occurs. The NPCs and membranes are associated with and supported by the lamina, which is composed mainly of a filamentous meshwork of type V intermediate filament proteins, the nuclear lamins, and dozens of associated proteins (2). Lamins are also found in lesser amounts throughout the nucleoplasm (3, 4).Nuclear lamins are the products of three genes: one gene encoding two A-type lamins and two genes encoding B-type lamins. The two A-type lamins, lamins A and C, are the result of alternative splicing of a single transcript of the LMNA gene (5). The two B-type lamins, lamins B1 and B2, and lamin A are farnesylated at their C termini. Although lamins B1 and B2 retain this modification for their lifetimes, mature lamin A is formed following a proteolytic cleavage to remove the lipid moiety and the C-terminal 15 amino acid residues (6). Both Aand B-type lamins are developmentally regulated, with B-type lamins expressed in all cells from the egg to terminally differentiated adult cells, whereas A-type lamins are expressed only at or after gastrulation (7) and then only in a subset of cell types. Both A-and B-type lamins are involved in the regulation of trans...

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Functions and dysfunctions of the nuclear lamin Ig-fold domain in nuclear assembly, growth, and Emery–Dreifuss muscular dystrophy

Cited by 49 publications

References 54 publications

Nuclear lamins: key regulators of nuclear structure and activities

Nuclear lamins: key regulators of nuclear structure and activities

The role ofDrosophilaLamin C in muscle function and gene expression

Regulation of Nuclear Lamin Polymerization by Importin α

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