scholarly journals Chain reaction: LINC complexes and nuclear positioning

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 136 ◽  
Author(s):  
Brian Burke
Keyword(s):  
Nuclear Membrane ◽  
Nuclear Periphery ◽  
Cell Types ◽  
Linc Complex ◽  
Nuclear Movement ◽  
Nuclear Positioning ◽  
Cell Architecture ◽  
Nuclear Location ◽  
Complex Regulation ◽  
Nuclear Structures

Nuclear positioning plays an essential role in defining cell architecture and behaviour in both development and disease, and nuclear location frequently adjusts according to internal and external cues. For instance, during periods of migration in many cell types, the nucleus may be actively repositioned behind the microtubule-organising centre. Nuclear movement, for the most part, is dependent upon coupling of the cytoskeleton to the nuclear periphery. This is accomplished largely through SUN and KASH domain proteins, which together assemble to form LINC (linker of the nucleoskeleton and cytoskeleton) complexes spanning the nuclear envelope. SUN proteins of the inner nuclear membrane provide a connection to nuclear structures while acting as a tether for outer nuclear membrane KASH proteins. The latter contain binding sites for diverse cytoskeletal components. Recent publications highlight new aspects of LINC complex regulation revealing that the interplay between SUN and KASH partners can strongly influence how the nucleus functionally engages with different branches of the cytoskeleton.

scholarly journals Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 170 ◽  
Author(s):  
Elisabetta Mattioli ◽  
Marta Columbaro ◽  
Mohammed Hakim Jafferali ◽  
Elisa Schena ◽  
Einar Hallberg ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Membrane Protein ◽  
Nuclear Envelope ◽  
Muscle Cell ◽  
Nuclear Periphery ◽  
Linc Complex ◽  
Cell Nuclei ◽  
Nuclear Movement ◽  
Prelamin A ◽  
Human Myotubes

LMNA linked-Emery-Dreifuss muscular dystrophy (EDMD2) is a rare disease characterized by muscle weakness, muscle wasting, and cardiomyopathy with conduction defects. The mutated protein lamin A/C binds several nuclear envelope components including the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the inner nuclear membrane protein Samp1 (Spindle Associated Membrane Protein 1). Considering that Samp1 is upregulated during muscle cell differentiation and it is involved in nuclear movement, we hypothesized that it could be part of the protein platform formed by LINC proteins and prelamin A at the myotube nuclear envelope and, as previously demonstrated for those proteins, could be affected in EDMD2. Our results show that Samp1 is uniformly distributed at the nuclear periphery of normal human myotubes and committed myoblasts, but its anchorage at the nuclear poles is related to the presence of farnesylated prelamin A and it is disrupted by the loss of prelamin A farnesylation. Moreover, Samp1 is absent from the nuclear poles in EDMD2 myotubes, which shows that LMNA mutations associated with muscular dystrophy, due to reduced prelamin A levels in muscle cell nuclei, impair Samp1 anchorage. Conversely, SUN1 pathogenetic mutations do not alter Samp1 localization in myotubes, which suggests that Samp1 lies upstream of SUN1 in nuclear envelope protein complexes. The hypothesis that Samp1 is part of the protein platform that regulates microtubule nucleation from the myotube nuclear envelope in concert with pericentrin and LINC components warrants future investigation. As a whole, our data identify Samp1 as a new contributor to EDMD2 pathogenesis and our data are relevant to the understanding of nuclear clustering occurring in laminopathic muscle.

scholarly journals Transcription-dependent spatial arrangements of CFTR and adjacent genes in human cell nuclei

2004 ◽  
Vol 166 (6) ◽  
pp. 815-825 ◽  
Author(s):  
Daniele Zink ◽  
Margarida D. Amaral ◽  
Andreas Englmann ◽  
Susanne Lang ◽  
Luka A. Clarke ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Human Cell ◽  
Transcriptional Activity ◽  
Nuclear Periphery ◽  
Cell Types ◽  
Dependent Manner ◽  
Cell Nuclei ◽  
Nuclear Positioning ◽  
Nuclear Environment ◽  
Nuclear Regions

We investigated in different human cell types nuclear positioning and transcriptional regulation of the functionally unrelated genes GASZ, CFTR, and CORTBP2, mapping to adjacent loci on human chromosome 7q31. When inactive, GASZ, CFTR, and CORTBP2 preferentially associated with the nuclear periphery and with perinuclear heterochromatin, whereas in their actively transcribed states the gene loci preferentially associated with euchromatin in the nuclear interior. Adjacent genes associated simultaneously with these distinct chromatin fractions localizing at different nuclear regions, in accordance with their individual transcriptional regulation. Although the nuclear localization of CFTR changed after altering its transcription levels, the transcriptional status of CFTR was not changed by driving this gene into a different nuclear environment. This implied that the transcriptional activity affected the nuclear positioning, and not vice versa. Together, the results show that small chromosomal subregions can display highly flexible nuclear organizations that are regulated at the level of individual genes in a transcription-dependent manner.

scholarly journals Mena regulates the LINC complex to control actin–nuclear lamina associations, trans-nuclear membrane signalling and cancer gene expression

2021 ◽  
Author(s):  
Frederic Li Mow Chee ◽  
Bruno Beernaert ◽  
Alexander E P Loftus ◽  
Yatendra Kumar ◽  
Billie G C Griffith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Envelope ◽  
Cancer Progression ◽  
Nuclear Membrane ◽  
Regulatory Protein ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
Actin Binding ◽  
Cancer Gene ◽  
Linc Complex

Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes (IACs), play key roles in cancer progression and metastasis. We investigated systems-level changes in the integrin adhesome during metastatic progression of a patient-derived cutaneous squamous cell carcinoma (cSCC), and found that the actin regulatory protein Mena is enriched in IACs in metastatic cSCC cells. Mena is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2, with which it interacts and co-localises at the nuclear envelope of metastatic cells. Moreover, Mena potentiates the interactions of nesprin-2 with the actin cytoskeleton and the nuclear lamina. CRISPR-mediated Mena depletion causes altered nuclear morphology, reduces tyrosine phosphorylation of the nuclear membrane protein emerin and downregulates expression of the immunomodulatory gene PTX3 via the recruitment of its enhancer to the nuclear periphery. We have uncovered an unexpected novel role for Mena at the nuclear membrane, where it controls the LINC complex, nuclear architecture, chromatin repositioning and cancer gene expression. This is the first description of an adhesion protein regulating gene transcription via direct signalling across the nuclear envelope.

scholarly journals Ctdnep1 and Eps8L2 regulate dorsal actin cables for nuclear positioning during cell migration

2020 ◽  
Author(s):  
Francisco J. Calero-Cuenca ◽  
Daniel S. Osorio ◽  
Sreerama Chaitanya Sridhara ◽  
Yue Jiao ◽  
Jheimmy Diaz ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nuclear Envelope ◽  
Leading Edge ◽  
Cell Types ◽  
Linc Complex ◽  
Nuclear Positioning ◽  
Physiological Functions ◽  
Actin Cables ◽  
Different Cell Types

SummaryCells actively position their nuclei within the cytoplasm for multiple cellular and physiological functions. Different cell types position their nuclei away from the leading edge to migrate properly. In migrating fibroblasts, nuclear positioning is driven by dorsal actin cables connected to the nuclear envelope by the LINC complex on Transmembrane Actin-associated Nuclear (TAN) lines. How dorsal actin cables are organized to form TAN lines is unknown. Here, we report a role for Ctdnep1/Dullard, a nuclear envelope phosphatase, and the actin regulator Eps8L2, on nuclear positioning. We demonstrate that Ctdnep1 and Eps8L2 directly interact to regulate the formation and thickness of dorsal actin cables required for TAN lines engagement for nuclear positioning. Our work establishes a novel mechanism to locally regulate actin at the nuclear envelope for nuclear positioning.

scholarly journals Identification of new transmembrane proteins concentrated at the nuclear envelope using organellar proteomics of mesenchymal cells

2018 ◽  
Author(s):  
Li-Chun Cheng ◽  
Sabyasachi Baboo ◽  
Cory Lindsay ◽  
Liza Brusman ◽  
Salvador Martinez-Bartolomé ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Nuclear Periphery ◽  
Transmembrane Proteins ◽  
Nuclear Lamina ◽  
Cell Types ◽  
Nucleocytoplasmic Transport ◽  
Membrane Dynamics ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes

AbstractThe nuclear envelope (NE) is an endoplasmic reticulum (ER) subdomain that contains characteristic components dedicated to nuclear functions. These include nuclear pore complexes (NPCs) – the channels for nucleocytoplasmic transport, and the nuclear lamina (NL) – a scaffold for NE and chromatin organization at the nuclear periphery. Since numerous human diseases associated with NE/NL proteins occur in mesenchyme-derived cells, a more comprehensive characterization of proteins concentrated at the NE in these cell types is warranted. Accordingly, we used proteomics to analyze NE and other subcellular fractions isolated from mesenchymal stem cells and from differentiated adipocytes and myocytes. We evaluated the proteomics datasets to calculate relative protein enrichment in the NE fraction, using a spectral abundance-based scoring system that accurately described most benchmark proteins. We then examined five high-scoring transmembrane proteins expressed in all three cell types that were not previously known to be enriched at the NE. Using quantitative immunofluorescence microscopy to track ectopically expressed proteins, we validated that all five of these components are substantially concentrated at the NE of multiple cell types. One (Itprip) is exposed to the outer nuclear membrane, a second (Smpd4) is enriched at the NPC, and the three others (Mfsd10, Tmx4, and Arl6ip6) are suggested to reside in the inner nuclear membrane. Considering their sequences and other features, these proteins provide new focal points for studying the functions and membrane dynamics of the NE. Our datasets should be useful for identifying additional NE-concentrated proteins, and for evaluating candidates that are identified in screening.

Two-step regulation of centromere distribution by condensin II and the nuclear envelope proteins

2021 ◽  
Author(s):  
Takuya Sakamoto ◽  
Yuki Sakamoto ◽  
Stefan Grob ◽  
Tomoe Yamashita ◽  
Nanami Ito ◽  
...  
Keyword(s):  
Regulatory Mechanism ◽  
Nuclear Periphery ◽  
Biological Significance ◽  
Nuclear Lamina ◽  
Cell Types ◽  
Chromatin Organization ◽  
Genome Integrity ◽  
Strong Impact ◽  
Linc Complex ◽  
Control Of Gene Expression

Abstract The arrangement of centromeres within the nucleus differs among species and cell types. However, neither the mechanisms determining centromere distribution nor its biological significance are currently well understood. In this study, we demonstrate the importance of centromere distribution for the maintenance of genome integrity through the cytogenic and molecular analysis of mutants defective in centromere distribution. We propose a two-step regulatory mechanism that shapes the non-Rabl-like centromere distribution in Arabidopsis thaliana through condensin II and the linker of the nucleoskeleton and cytoskeleton (LINC) complex. Condensin II is enriched at centromeres and, in cooperation with the LINC complex, induces the scattering of centromeres around the nuclear periphery during late anaphase/telophase. Then, after entering interphase, the positions of the scattered centromeres are stabilized by nuclear lamina proteins of the CROWDED NUCLEI (CRWN) family. We also found that, despite their strong impact on centromere distribution, condensin II and CRWNs have little effect on chromatin organization involved in the control of gene expression, indicating the robustness of chromatin organization regardless of the type of centromere distribution.

scholarly journals Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ruth Jinfen Chai ◽  
Hendrikje Werner ◽  
Peter Yiqing Li ◽  
Yin Loon Lee ◽  
Khaing Thet Nyein ◽  
...  
Keyword(s):  
Cardiac Failure ◽  
Viral Vector ◽  
Nuclear Periphery ◽  
Dominant Negative ◽  
Gene Transduction ◽  
Linc Complex ◽  
Specific Expression ◽  
Common Cause ◽  
Complex Protein ◽  
One Year

AbstractMutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy. Here we show that mice with a cardiomyocyte-specific Lmna deletion develop cardiac failure and die within 3–4 weeks after inducing the mutation. When the same Lmna mutations are induced in mice genetically deficient in the LINC complex protein SUN1, life is extended to more than one year. Disruption of SUN1’s function is also accomplished by transducing and expressing a dominant-negative SUN1 miniprotein in Lmna deficient cardiomyocytes, using the cardiotrophic Adeno Associated Viral Vector 9. The SUN1 miniprotein disrupts binding between the endogenous LINC complex SUN and KASH domains, displacing the cardiomyocyte KASH complexes from the nuclear periphery, resulting in at least a fivefold extension in lifespan. Cardiomyocyte-specific expression of the SUN1 miniprotein prevents cardiomyopathy progression, potentially avoiding the necessity of developing a specific therapeutic tailored to treating each different LMNA cardiomyopathy-inducing mutation of which there are more than 450.

scholarly journals ELECTRON MICROSCOPY OF THE NUCLEAR MEMBRANE OF AMOEBA PROTEUS

1956 ◽  
Vol 2 (4) ◽  
pp. 445-448 ◽  
Author(s):  
Marie H. Greider ◽  
Wencel J. Kostir ◽  
Walter J. Frajola
Keyword(s):  
Electron Microscopy ◽  
Electron Microscope ◽  
Nuclear Membrane ◽  
Outer Layer ◽  
Microscope Study ◽  
Electron Microscope Study ◽  
Cell Types ◽  
Amoeba Proteus ◽  
Nuclear Membranes ◽  
Thin Sectioning

An electron microscope study of the nuclear membrane of Amoeba proteus by thin sectioning techniques has revealed an ultrastructure in the outer layer of the membrane that is homologous to the pores and annuli observed in the nuclear membranes of many other cell types studied by these techniques. An inner honeycombed layer apparently unique to Amoeba proteus is also described.

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