Enucleated cells reveal differential roles of the nucleus in cell migration, polarity, and mechanotransduction

Graham, David M.; Andersen, Torben; Sharek, Lisa; Uzer, Gunes; Rothenberg, Katheryn E.; Hoffman, Brenton D.; Rubin, Janet; Balland, Martial; Bear, James E.; Burridge, Keith

doi:10.1083/jcb.201706097

Cited by 104 publications

(127 citation statements)

References 84 publications

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“…Migration through a constriction provides unique mechanical challenges [33]. Due to its size and stiffness, the nucleus is the rate limiting step for size reduction [18,34], but it also provides a stiff internal surface for the cytoskeleton to 'push' on and generate force [35]. Nuclear positioning during migration is tightly controlled by the cytoskeleton, and it is usually positioned towards the back of the cell [36].…”

Section: Introductionmentioning

confidence: 99%

Migration through a small pore disrupts inactive chromatin organization in neutrophil-like cells

Jacobson

Perry

Long

et al. 2018

Preprint

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BackgroundMammalian cells are flexible and can rapidly change shape when they contract, adhere, or migrate. Their nucleus must be stiff enough to withstand cytoskeletal forces, but flexible enough to remodel as the cell changes shape. This is particularly important for cells migrating through constricted space, where the nuclear shape must change in order to fit through the constriction. This occurs many times in the life cycle of a neutrophil, which must protect its chromatin from damage and disruption associated with migration.

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Section: Introductionmentioning

confidence: 99%

Migration through a small pore disrupts inactive chromatin organization in neutrophil-like cells

Jacobson

Perry

Long

et al. 2018

Preprint

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“…In non-differentiated cells, and notably in cells proliferating in culture, the force balance is believed to set the centrosome position at the cell geometrical center, also called center of mass or centroid [24][25][26]. Microtubule-based forces in an in vitro reconstituted system also position the MTOC at the centroid of their confinement area [14,15,[27][28][29].…”

Section: Introductionmentioning

confidence: 99%

“…It has been a considerable limitation for the study of centrosome positioning in anisotropic conditions such as in migrating cells [33,34]. Both the nucleus and the centrosome have their own self-centering properties [26,[34][35][36] see (for Reviews [37,38]).…”

Section: Introductionmentioning

confidence: 99%

“…For these reasons, enucleated cells -here referred as cytoplasts -offered an interesting possibility to untangle the geometrical and molecular cues that specifically control centrosome position. Plating them on on adhesive micropatterns revealed that centrosome self-positions at the geometrical center of the cytoplasts suggesting that its off-centering in cells is due to microtubule interaction with the nucleus [26,34]. However, the centrosome often detaches from the nucleus when moving to the cell periphery during the migration of neuroblasts [47] or epithelium formation [48] for example.…”

Section: Introductionmentioning

confidence: 99%

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Acto-myosin network geometry defines centrosome position

Jiménez

Pascalis

Letort

et al. 2020

Preprint

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The centrosome is the main organizer of microtubules and as such, its position is a key determinant of polarized cell functions. As the name says, the default position of the centrosome is considered to be the cell geometrical center. However, the mechanism regulating centrosome positioning is still unclear and often confused with the mechanism regulating the position of the nucleus to which it is linked. Here we used enucleated cells plated on adhesive micropatterns to impose regular and precise geometrical conditions to centrosome-microtubule networks. Although frequently observed there, the equilibrium position of the centrosome is not systematically at the cell geometrical center and can be close to cell edge. Centrosome positioning appears to respond accurately to the architecture and anisotropy of the actin network, which constitutes, rather than cell shape, the actual spatial boundary conditions the microtubule network is sensitive to. We found that the contraction of the actin network defines a peripheral margin, in which microtubules appeared bent by compressive forces. The disassembly of the actin network away from the cell edges defines an inner zone where actin bundles were absent and microtubules were more radially organized.The production of dynein-based forces on microtubules places the centrosome at the center of this inner zone. Cell adhesion pattern and contractile forces define the shape and position of the inner zone in which the centrosome-microtubule network is centered.

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“…Durotaxis is a type of directional cell migration in which cells respond to a gradient of extracellular stiffness 13,14 . Mechanisms underlying durotaxis of mesenchymal cells are proposed to include contractile mechanosensation, probing of the local substrate by actin-based protrusions, and focal adhesion signaling [15][16][17][18][19][20][21] . Force fluctuations within individual FAs have been observed to mediate ECM-rigidity sensing in guiding directed cell migration 15 .…”

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confidence: 99%

LIMD1 phase separation contributes to cellular mechanics and durotaxis by regulating focal adhesion dynamics in response to force

Wang

Zhang

Shao

et al. 2019

Preprint

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Abstract：The mechanical environement affects cell morphology, differentiation and motility. The ability of cells to follow gradients of extracellular matrix stiffness-durotaxis has been implicated in development, fibrosis, and cancer. Cells sense and respond to extra-cellular mechanical cues through cell-matrix adhesions. Interestingly, the maturation of focal adhesions (FAs) is reciprocally force-dependent. How biomechanical cues dictate the status of cell motility and how FAs coordinate force sensing and self-organization remain enigmatic. LIMD1, a member of the LIM domain proteins, localizes to the FAs and has been reported to negatively regulate the Hippo-YAP pathway in response to tension. Here we identify the force sensitive recruitment of LIMD1 to the FAs. We discover that LIMD1 regulates cell spreading, maintains FA dynamics and cellular force, and is critical for durotaxis. Intriguingly, LIMD1 selectively recruits late but not early FA proteins through phase separation at the FAs under force. We suggest a model in which localization of LIMD1 to the FAs, triggered by mechanical force, serves as a phase separation hub for assembling and organizing late FA proteins, allowing for effective FA maturation and efficient cellular mechano-transduction.Force transmission from the extracellular environment to the interior of a cell has been a fascinating subject for decades. Integrin mediated adhesion sites bind to extracellular molecules and initiate a cascade of molecular assembly underneath the plasma membrane, constructing a highly organized structure that is capable of transducing mechanical force 1 . These adhesion sites have been extensively investigated for their crucial roles in mediating both inside-out and outside-in signaling which are essential for cell survival and motility 1-5 . Focal adhesions (FAs) are cell-matrix contacts that mature from nascent focal complexes containing integrins and a few other molecules such as kindlin, talin, FAK and paxillin 6-8 . Only a portion of the nascent focal complexes survives the maturation process and during that they grow by rapidly recruiting late FA proteins to assemble plaque like structures and clutching to the actin stress fibers. Matured FAs exhibited ordered ultrastructure with the force transmission layer sandwiched between the integrin layer and the actin association layer 9 . Specific protein-protein interactions have been identified to participate in FA maturation 10-12 . However, how the army of FA proteins achieves spatial-temporally controlled recruitment and assembly remains unveiled.Efficient force transmission through the FAs is essential for numerous cellular processes including cell migration. Durotaxis is a type of directional cell migration in which cells respond to a gradient of extracellular stiffness 13,14 . Mechanisms underlying durotaxis of mesenchymal cells are proposed to include contractile mechanosensation, probing of the local substrate by actin-based protrusions, and focal adhesion signaling [15][16][17][18][19][20][21] . Force flu...

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Enucleated cells reveal differential roles of the nucleus in cell migration, polarity, and mechanotransduction

Cited by 104 publications

References 84 publications

Migration through a small pore disrupts inactive chromatin organization in neutrophil-like cells

Migration through a small pore disrupts inactive chromatin organization in neutrophil-like cells

Acto-myosin network geometry defines centrosome position

LIMD1 phase separation contributes to cellular mechanics and durotaxis by regulating focal adhesion dynamics in response to force

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