scholarly journals A cooperative network at the nuclear envelope counteracts LINC-mediated forces during oogenesis in C. elegans

2021 ◽  
Author(s):  
Chenshu Liu ◽  
Zoe Lung ◽  
John S Wang ◽  
Fan Wu ◽  
Abby F Dernburg
Keyword(s):  
Nuclear Envelope ◽  
Mechanical Stress ◽  
Oocyte Maturation ◽  
Nuclear Membrane ◽  
Mechanical Forces ◽  
Linc Complex ◽  
Cooperative Network ◽  
C Elegans ◽  
Stressful Environment ◽  
Balance Of Forces

Oogenesis involves meiosis and oocyte maturation. Both processes rely on mechanical forces (Lee et al., 2015; Nagamatsu et al., 2019; Rog and Dernburg, 2015; Sato et al., 2009; Tsatskis et al., 2020; Wynne et al., 2012), which can be transduced from the cytoskeleton to the nuclear envelope (NE) through linker of nucleoskeleton and cytoskeleton (LINC) complexes (Burke, 2018; Chang et al., 2015; Fan et al., 2020; Link et al., 2014). Gametes must protect their genomes from damage in this mechanically stressful environment. In C. elegans, oocyte nuclei lacking the single lamin protein LMN-1 are vulnerable to nuclear collapse. Here we deploy the auxin-inducible degradation system to investigate the balance of forces that drive this collapse and protect oocyte nuclei. We find that nuclear collapse is not a consequence of apoptosis. It is promoted by dynein and a LINC complex comprised of SUN-1 and ZYG-12, which assumes polarized distribution at the NE in response to dynein-mediated forces. We also show that the lamin meshwork works in parallel with other inner nuclear membrane (INM) proteins to counteract mechanical stress at the NE during oogenesis. We speculate that a similar network may protect oocyte integrity during the long arrest period in mammals.

scholarly journals The Caenorhabditis elegans SUN protein UNC-84 interacts with lamin to transfer forces from the cytoplasm to the nucleoskeleton during nuclear migration

2014 ◽  
Vol 25 (18) ◽  
pp. 2853-2865 ◽  
Author(s):  
Courtney R. Bone ◽  
Erin C. Tapley ◽  
Mátyás Gorjánácz ◽  
Daniel A. Starr
Keyword(s):  
Caenorhabditis Elegans ◽  
Nuclear Envelope ◽  
Missense Mutation ◽  
Nuclear Membrane ◽  
Nuclear Migration ◽  
Live Imaging ◽  
Mechanical Forces ◽  
The Sun ◽  
Critical Component ◽  
Linc Complex

Nuclear migration is a critical component of many cellular and developmental processes. The nuclear envelope forms a barrier between the cytoplasm, where mechanical forces are generated, and the nucleoskeleton. The LINC complex consists of KASH proteins in the outer nuclear membrane and SUN proteins in the inner nuclear membrane that bridge the nuclear envelope. How forces are transferred from the LINC complex to the nucleoskeleton is poorly understood. The Caenorhabditis elegans lamin, LMN-1, is required for nuclear migration and interacts with the nucleoplasmic domain of the SUN protein UNC-84. This interaction is weakened by the unc-84(P91S) missense mutation. These mutant nuclei have an intermediate nuclear migration defect—live imaging of nuclei or LMN-1::GFP shows that many nuclei migrate normally, others initiate migration before subsequently failing, and others fail to begin migration. At least one other component of the nucleoskeleton, the NET5/Samp1/Ima1 homologue SAMP-1, plays a role in nuclear migration. We propose a nut-and-bolt model to explain how forces are dissipated across the nuclear envelope during nuclear migration. In this model, SUN/KASH bridges serve as bolts through the nuclear envelope, and nucleoskeleton components LMN-1 and SAMP-1 act as both nuts and washers on the inside of the nucleus.

scholarly journals Nuclear envelope rupture is induced by actin-based nucleus confinement

2016 ◽  
Vol 215 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Emily M. Hatch ◽  
Martin W. Hetzer
Keyword(s):  
Nuclear Envelope ◽  
Cancer Cells ◽  
Nuclear Membrane ◽  
Nuclear Lamina ◽  
Membrane Stability ◽  
Linc Complex ◽  
Actin Bundles ◽  
In Cells

Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias. Finally, NE rupture inhibition could be rescued in cells treated with actin-depolymerizing drugs by mechanically constraining nucleus height. These data suggest a model of NE rupture where weak membrane areas, caused by defects in lamina organization, rupture because of an increase in intranuclear pressure from actin-based nucleus confinement.

scholarly journals A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte

2020 ◽  
Vol 126 (3) ◽  
Author(s):  
Julie Heffler ◽  
Parisha P. Shah ◽  
Patrick Robison ◽  
Sai Phyo ◽  
Kimberly Veliz ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Intermediate Filaments ◽  
Genome Organization ◽  
Contractile Function ◽  
Nuclear Architecture ◽  
Super Resolution ◽  
Nuclear Lamina ◽  
Linc Complex ◽  
Spectrin Repeat ◽  
Balance Of Forces

Rationale: Mechanical forces are transduced to nuclear responses via the linkers of the nucleoskeleton and cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleoskeleton to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Furthermore, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown. Objective: Here, we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte. Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin [nuclear envelope spectrin repeat protein]-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies. Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte.

scholarly journals Nuclear envelope organization in Dictyostelium discoideum

2019 ◽  
Vol 63 (8-9-10) ◽  
pp. 509-519 ◽  
Author(s):  
Petros Batsios ◽  
Ralph Gräf ◽  
Michael P. Koonce ◽  
Denis A. Larochelle ◽  
Irene Meyer
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Nuclear Lamina ◽  
Major Constituent ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Linc Complex ◽  
Family Protein ◽  
Import And Export ◽  
Pore Complexes

The nuclear envelope consists of the outer and the inner nuclear membrane, the nuclear lamina and the nuclear pore complexes, which regulate nuclear import and export. The major constituent of the nuclear lamina of Dictyostelium is the lamin NE81. It can form filaments like B-type lamins and it interacts with Sun1, as well as with the LEM/HeH-family protein Src1. Sun1 and Src1 are nuclear envelope transmembrane proteins involved in the centrosome-nucleus connection and nuclear envelope stability at the nucleolar regions, respectively. In conjunction with a KASH-domain protein, Sun1 usually forms a so-called LINC complex. Two proteins with functions reminiscent of KASH-domain proteins at the outer nuclear membrane of Dictyostelium are known; interaptin which serves as an actin connector and the kinesin Kif9 which plays a role in the microtubule-centrosome connector. However, both of these lack the conserved KASH-domain. The link of the centrosome to the nuclear envelope is essential for the insertion of the centrosome into the nuclear envelope and the appropriate spindle formation. Moreover, centrosome insertion is involved in permeabilization of the mitotic nucleus, which ensures access of tubulin dimers and spindle assembly factors. Our recent progress in identifying key molecular players at the nuclear envelope of Dictyostelium promises further insights into the mechanisms of nuclear envelope dynamics.

scholarly journals Decreased torsinA or LINC Complex Function Rescues a Laminopathy in Caenorhabditis elegans

2020 ◽  
Author(s):  
Gabriela Huelgas-Morales ◽  
Mark Sanders ◽  
Gemechu Mekonnen ◽  
Tatsuya Tsukamoto ◽  
David Greenstein
Keyword(s):  
Nuclear Envelope ◽  
Complex Function ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Linc Complex ◽  
Force Transmission ◽  
Complex Activity ◽  
Aaa Atpase ◽  
C Elegans ◽  
Associated Proteins

AbstractThe function of the nucleus depends on the integrity of the nuclear lamina, an intermediate filament network associated with the linker of nucleoskeleton and cytoskeleton (LINC) complex spanning the nuclear envelope. In turn, the AAA+ ATPase torsinA regulates force transmission from the cytoskeleton to the nucleus. In humans, mutations affecting nuclear envelope-associated proteins cause laminopathies, including progeria, myopathy, and dystonia. We report that decreasing the function of the C. elegans torsinA homolog, OOC-5, rescues the sterility and premature aging caused by a null mutation in the single worm lamin homolog, lmn-1. Loss of OOC-5 activity prevents nuclear collapse in lmn-1 mutants by disrupting the function of the LINC complex. These results suggest that LINC complex-transmitted forces damage nuclei with a compromised nuclear lamina.One Sentence SummaryInhibiting LINC complex activity prevents a progeric syndrome in C. elegans.

scholarly journals The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms

2021 ◽  
Author(s):  
Yuanyuan Zhang ◽  
Evelyn Hutterer ◽  
Sara Hultin ◽  
Otto Bergman ◽  
Maria Forteza ◽  
...  
Keyword(s):  
Nuclear Membrane ◽  
Actin Filaments ◽  
Fluid Shear Stress ◽  
Abdominal Aortic Aneurysms ◽  
Normal Diet ◽  
Aortic Aneurysms ◽  
Cell Junctions ◽  
Mechanical Forces ◽  
Linc Complex ◽  
Abdominal Aortic

Abstract Arterial endothelial cells (ECs) have the ability to respond to mechanical forces exerted by fluid shear stress. This response is of importance, as it is protective against vascular diseases such as atherosclerosis and aortic aneurysms. Mechanical forces are transmitted at the sites of adhesion to the basal membrane as well as cell-cell junctions where protein complexes connect to the cellular cytoskeleton to relay force into the cell. Here we present a novel protein complex that connects junctional VE-cadherin and radial actin filaments to the LINC complex in the nuclear membrane. We show that the scaffold protein AmotL2 is essential for the formation of radial actin filaments and the flow-induced alignment of aortic and arterial ECs. The deletion of endothelial AmotL2 alters nuclear shape as well as subcellular positioning. Molecular analysis shows that VE-cadherin is mechanically associated with the nuclear membrane via binding to AmotL2 and Actin. Furthermore, the deletion of AmotL2 in ECs provokes a pro-inflammatory response and abdominal aortic aneurysms (AAA) in the aorta of mice on a normal diet. Remarkably, transcriptome analysis of AAA samples from human patients revealed a negative correlation between AmotL2 expression and aneurysm diameters, as well as a positive correlation between AmotL2 and YAP expression. These findings provide a conceptual framework regarding how mechanotransduction in the junctions is coupled with vascular disease.

scholarly journals Decreased mechanotransduction prevents nuclear collapse in aCaenorhabditis eleganslaminopathy

2020 ◽  
Vol 117 (49) ◽  
pp. 31301-31308
Author(s):  
Gabriela Huelgas-Morales ◽  
Mark Sanders ◽  
Gemechu Mekonnen ◽  
Tatsuya Tsukamoto ◽  
David Greenstein
Keyword(s):  
Nuclear Envelope ◽  
Complex Function ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Nuclear Pore ◽  
Linc Complex ◽  
Force Transmission ◽  
Cell Nuclei ◽  
Aaa Atpase ◽  
C Elegans

The function of the nucleus depends on the integrity of the nuclear lamina, an intermediate filament network associated with the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex spans the nuclear envelope and mediates nuclear mechanotransduction, the process by which mechanical signals and forces are transmitted across the nuclear envelope. In turn, the AAA+ ATPase torsinA is thought to regulate force transmission from the cytoskeleton to the nucleus. In humans, mutations affecting nuclear envelope-associated proteins cause laminopathies, including progeria, myopathy, and dystonia, though the extent to which endogenous mechanical stresses contribute to these pathologies is unclear. Here, we use theCaenorhabditis elegansgermline as a model to investigate mechanisms that maintain nuclear integrity as germ cell nuclei progress through meiotic development and migrate for gametogenesis—processes that require LINC complex function. We report that decreasing the function of theC. eleganstorsinA homolog, OOC-5, rescues the sterility and premature aging caused by a null mutation in the single worm lamin homolog. We show that decreasing OOC-5/torsinA activity prevents nuclear collapse in lamin mutants by disrupting the function of the LINC complex. At a mechanistic level, OOC-5/torsinA promotes the assembly or maintenance of the lamin-associated LINC complex and this activity is also important for interphase nuclear pore complex insertion into growing germline nuclei. These results demonstrate that LINC complex-transmitted forces damage nuclei with a compromised nuclear lamina. Thus, the torsinA–LINC complex nexus might comprise a therapeutic target for certain laminopathies by preventing damage from endogenous cellular forces.

scholarly journals A network of nuclear envelope proteins and cytoskeletal force generators mediates movements of and within nuclei throughout Caenorhabditis elegans development

2019 ◽  
Vol 244 (15) ◽  
pp. 1323-1332 ◽  
Author(s):  
Daniel A Starr
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Dna Damage Repair ◽  
Nuclear Migration ◽  
Envelope Proteins ◽  
Nuclear Positioning ◽  
C Elegans ◽  
Damage Repair

Nuclear migration and anchorage, together referred to as nuclear positioning, are central to many cellular and developmental events. Nuclear positioning is mediated by a conserved network of nuclear envelope proteins that interacts with force generators in the cytoskeleton. At the heart of this network are linker of nucleoskeleton and cytoskeleton (LINC) complexes made of Sad1 and UNC-84 (SUN) proteins at the inner nuclear membrane and Klarsicht, ANC-1, and Syne homology (KASH) proteins in the outer nuclear membrane. LINC complexes span the nuclear envelope, maintain nuclear envelope architecture, designate the surface of nuclei distinctly from the contiguous endoplasmic reticulum, and were instrumental in the early evolution of eukaryotes. LINC complexes interact with lamins in the nucleus and with various cytoplasmic KASH effectors from the surface of nuclei. These effectors regulate the cytoskeleton, leading to a variety of cellular outputs including pronuclear migration, nuclear migration through constricted spaces, nuclear anchorage, centrosome attachment to nuclei, meiotic chromosome movements, and DNA damage repair. How LINC complexes are regulated and how they function are reviewed here. The focus is on recent studies elucidating the best-understood network of LINC complexes, those used throughout Caenorhabditis elegans development. Impact statement Defects in nuclear positioning disrupt development in many mammalian tissues. In human development, LINC complexes play important cellular functions including nuclear positioning, homolog pairing in meiosis, DNA damage repair, wound healing, and gonadogenesis. The topics reviewed here are relevant to public health because defects in nuclear positioning and mutations in LINC components are associated with a wide variety of human diseases including muscular dystrophies, neurological disorders, progeria, aneurysms, hearing loss, blindness, sterility, and multiple cancers. Although this review focuses on findings in the model nematode Caenorhabditis elegans, the studies are relevant because almost all the findings originally made in C. elegans are conserved to humans. Furthermore, C. elegans remains the best described network for how LINC complexes are regulated and function.

scholarly journals Outer nuclear membrane protein Kuduk modulates the LINC complex and nuclear envelope architecture

2017 ◽  
Vol 216 (9) ◽  
pp. 2827-2841 ◽  
Author(s):  
Zhao-Ying Ding ◽  
Ying-Hsuan Wang ◽  
Yu-Cheng Huang ◽  
Myong-Chol Lee ◽  
Min-Jen Tseng ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Control Mechanism ◽  
Genetic Data ◽  
Linc Complex ◽  
Outer Nuclear Membrane ◽  
Functional Conservation ◽  
Evolutionarily Conserved ◽  
Human Orthologue ◽  
Quality Control Mechanism

Linker of nucleoskeleton and cytoskeleton (LINC) complexes spanning the nuclear envelope (NE) contribute to nucleocytoskeletal force transduction. A few NE proteins have been found to regulate the LINC complex. In this study, we identify one, Kuduk (Kud), which can reside at the outer nuclear membrane and is required for the development of Drosophila melanogaster ovarian follicles and NE morphology of myonuclei. Kud associates with LINC complex components in an evolutionarily conserved manner. Loss of Kud increases the level but impairs functioning of the LINC complex. Overexpression of Kud suppresses NE targeting of cytoskeleton-free LINC complexes. Thus, Kud acts as a quality control mechanism for LINC-mediated nucleocytoskeletal connections. Genetic data indicate that Kud also functions independently of the LINC complex. Overexpression of the human orthologue TMEM258 in Drosophila proved functional conservation. These findings expand our understanding of the regulation of LINC complexes and NE architecture.

scholarly journals Uniaxial loading induces a scalable switch in cortical actomyosin flow polarization and reveals mechanosensitive regulation of cytokinesis

2019 ◽  
Author(s):  
Deepika Singh ◽  
Devang Odedra ◽  
Christian Pohl
Keyword(s):  
Cell Division ◽  
Stress Response ◽  
Mechanical Stress ◽  
Rotational Flow ◽  
Mechanical Forces ◽  
Longitudinal Flow ◽  
Contractile Ring ◽  
Animal Development ◽  
C Elegans ◽  
Cortical Fibers

AbstractDuring animal development, it is crucial that cells can sense and adapt to mechanical forces from their environment. Ultimately, these forces are transduced through the actomyosin cortex. How the cortex can simultaneously respond to and create forces during cytokinesis is not well understood. Here we show that under mechanical stress, cortical actomyosin flow switches its polarization during cytokinesis in the C. elegans embryo. In unstressed embryos, longitudinal cortical flows contribute to contractile ring formation, while rotational cortical flow is additionally induced in uniaxially loaded embryos. Rotational cortical flow is required for the redistribution of the actomyosin cortex in loaded embryos. Rupture of longitudinally aligned cortical fibers during cortex rotation releases tension, initiates orthogonal longitudinal flow and thereby contributes to furrowing in loaded embryos. A targeted screen for factors required for rotational flow revealed that actomyosin regulators involved in RhoA regulation, cortical polarity and chirality are all required for rotational flow and become essential for cytokinesis under mechanical stress. In sum, our findings extend the current framework of mechanical stress response during cell division and show scaling of orthogonal cortical flows to the amount of mechanical stress.

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