Cancer cell migration through narrow constrictions generates compressive stresses on the nucleus that deform it and cause rupture of nuclear membranes. Nuclear membrane rupture allows uncontrolled exchange between nuclear and cytoplasmic contents. Local tensile stresses can also cause nuclear deformations, but whether such deformations are accompanied by nuclear membrane rupture is unknown. Here we used a direct force probe to locally deform the nucleus by applying a transient tensile stress to the nuclear membrane. We found that a transient (∼0.2 s) deformation (∼1% projected area strain) in normal mammary epithelial cells (MCF-10A cells) was sufficient to cause rupture of the nuclear membrane. Nuclear membrane rupture scaled with the magnitude of nuclear deformation and the magnitude of applied tensile stress. Comparison of diffusive fluxes of nuclear probes between wild-type and lamin-depleted MCF-10A cells revealed that lamin A/C, but not lamin B2, protects the nuclear membranes against rupture from tensile stress. Our results suggest that transient nuclear deformations typically caused by local tensile stresses are sufficient to cause nuclear membrane rupture.
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Nuclear Structure at the Crossroads
Abstract Steven Weinberg’s seminal papers from 1990–92 initiated the use of effective field theories (EFTs) for nuclei. We summarize progress, priorities, and open questions for nuclear EFT developments based on the 2019 INT program “Nuclear Structure at the Crossroads.”
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- Award ID(s):
- 1913069
- NSF-PAR ID:
- 10334917
- Date Published:
- Journal Name:
- Few-Body Systems
- Volume:
- 62
- Issue:
- 3
- ISSN:
- 0177-7963
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Cells migrate in vivo through complex confining microenvironments, which induce significant nuclear deformation that may lead to nuclear blebbing and nuclear envelope rupture. While actomyosin contractility has been implicated in regulating nuclear envelope integrity, the exact mechanism remains unknown. Here, we argue that confinement-induced activation of RhoA/myosin-II contractility, coupled with LINC complex-dependent nuclear anchoring at the cell posterior, locally increases cytoplasmic pressure and promotes passive influx of cytoplasmic constituents into the nucleus without altering nuclear efflux. Elevated nuclear influx is accompanied by nuclear volume expansion, blebbing, and rupture, ultimately resulting in reduced cell motility. Moreover, inhibition of nuclear efflux is sufficient to increase nuclear volume and blebbing on two-dimensional surfaces, and acts synergistically with RhoA/myosin-II contractility to further augment blebbing in confinement. Cumulatively, confinement regulates nuclear size, nuclear integrity, and cell motility by perturbing nuclear flux homeostasis via a RhoA-dependent pathway.
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Nuclear reactor safety is unique in that even after an incident is identified and the reactor shut down, the possibility of damage to people and environment does not stop: there is a long tail to the incident due to decay heat and potential for radiation leakage, which must also be contained properly, as exemplified in Fukushima where most radiation releases happened after initial earthquake and plant shut-down. Nuclear reactors generate close to 20% of the energy required by our nation. There is increasing interest in nuclear power as a low emissions alternative to fossil fuel-based power. Investments in the next generation of nuclear power plants include many nuclear startups such as NuScale and high-profile investments by Bill Gates’ Terra Power. Nuclear reactor operators are critical personnel who operate nuclear reactors, monitor the health of the operation, and are the first line of defense in case of an incident. Though the Nuclear Regulatory Commission creates and maintains standards and procedures for nuclear safety, their programmatic mandate involves are focused on existing technology, in the form of commercial nuclear power plants and other uses of nuclear materials through licensing, inspection and enforcement activities. This report summarizes the collected thoughts and insights from a diverse working group on the intersection of next generation technology with the training of future nuclear reactor operators.more » « less
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Chromatin is an essential component of nuclear mechanical response and shape that maintains nuclear compartmentalization and function. However, major genomic functions, such as transcription activity, might also impact cell nuclear shape via blebbing and rupture through their effects on chromatin structure and dynamics. To test this idea, we inhibited transcription with several RNA polymerase II inhibitors in wild type cells and perturbed cells that present increased nuclear blebbing. Transcription inhibition suppresses nuclear blebbing for several cell types, nuclear perturbations, and transcription inhibitors. Furthermore, transcription inhibition suppresses nuclear bleb formation, bleb stabilization, and bleb-based nuclear ruptures. Interestingly, transcription inhibition does not alter either H3K9 histone modification state, nuclear rigidity, or actin compression and contraction, which typically control nuclear blebbing. Polymer simulations suggest that RNA pol II motor activity within chromatin could drive chromatin motions that deform the nuclear periphery. Our data provide evidence that transcription inhibition suppresses nuclear blebbing and rupture, separate and distinct from chromatin rigidity.
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Abstract Mesenchymal stem cells (MSCs) respond to environmental forces with both cytoskeletal re-structuring and activation of protein chaperones of mechanical information, β-catenin, and yes-associated protein 1 (YAP1). To function, MSCs must differentiate between dynamic forces such as cyclic strains of extracellular matrix due to physical activity and static strains due to ECM stiffening. To delineate how MSCs recognize and respond differently to both force types, we compared effects of dynamic (200 cycles × 2%) and static (1 × 2% hold) strain on nuclear translocation of β-catenin and YAP1 at 3 hours after force application. Dynamic strain induced nuclear accumulation of β-catenin, and increased cytoskeletal actin structure and cell stiffness, but had no effect on nuclear YAP1 levels. Critically, both nuclear actin and nuclear stiffness increased along with dynamic strain-induced β-catenin transport. Augmentation of cytoskeletal structure using either static strain or lysophosphatidic acid did not increase nuclear content of β-catenin or actin, but induced robust nuclear increase in YAP1. As actin binds β-catenin, we considered whether β-catenin, which lacks a nuclear localization signal, was dependent on actin to gain entry to the nucleus. Knockdown of cofilin-1 (Cfl1) or importin-9 (Ipo9), which co-mediate nuclear transfer of G-actin, prevented dynamic strain-mediated nuclear transfer of both β-catenin and actin. In sum, dynamic strain induction of actin re-structuring promotes nuclear transport of G-actin, concurrently supporting nuclear access of β-catenin via mechanisms used for actin transport. Thus, dynamic and static strain activate alternative mechanoresponses reflected by differences in the cellular distributions of actin, β-catenin, and YAP1.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1007/s00601-021-01658-5
