Kinesin-1 and dynein at the nuclear envelope mediate the bidirectional migrations of nuclei

Fridolfsson, Heidi N.; Starr, Daniel A.

doi:10.1083/jcb.201004118

Cited by 146 publications

(177 citation statements)

References 73 publications

(132 reference statements)

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“…Because F-actin and microtubule motors are known to exert forces on the nuclear surface (2,5,6,18,(25)(26)(27)(28), it is surprising that they do not contribute to mechanical homeostasis of the nucleus. It seems that these cytoskeletal networks have the primary role of generating active forces through motor activity on the nuclear surface to position it.…”

Section: Discussionmentioning

confidence: 99%

Direct force probe reveals the mechanics of nuclear homeostasis in the mammalian cell

Neelam¹,

Chancellor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

126

175

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How cells maintain nuclear shape and position against various intracellular and extracellular forces is not well understood, although defects in nuclear mechanical homeostasis are associated with a variety of human diseases. We estimated the force required to displace and deform the nucleus in adherent living cells with a technique to locally pull the nuclear surface. A minimum pulling force of a few nanonewtons-far greater than typical intracellular motor forces-was required to significantly displace and deform the nucleus. Upon force removal, the original shape and position were restored quickly within a few seconds. This stiff, elastic response required the presence of vimentin, lamin A/C, and SUN (Sad1p, UNC-84)-domain protein linkages, but not F-actin or microtubules. Although F-actin and microtubules are known to exert mechanical forces on the nuclear surface through molecular motor activity, we conclude that the intermediate filament networks maintain nuclear mechanical homeostasis against localized forces.nuclear forces | cytoskeleton | nuclear positioning | nuclear mechanics | nuclear shape T he nucleus in a cultured cell such as a fibroblast is close to the center of the cell and typically has a smooth, regular shape. It is known that the migrating cell moves the nucleus by transferring cytoskeletal forces through connections between the cytoskeleton and the nuclear surface (1, 2). Even in a stationary cell, the nuclear shape and central position are stably maintained in mechanical homeostasis at defined locations in the cell, despite the fact that the dynamic cytoskeleton continues to generate constantly fluctuating forces on the nucleus (3, 4).The source of fluctuating forces on the nucleus includes nuclear-embedded microtubule motors such as dynein and kinesin (5-7) and actomyosin forces that push on and pull the nucleus (2,8,9). The nucleus is also exposed to extracellular forces, such as those applied to adhesion receptors, which can be transmitted through the cytoskeleton onto the nuclear surface (10-12). How nuclear shape and position are maintained in mechanical homeostasis despite the different types of forces that act on the nucleus is an open question. This is particularly important because deregulated positioning and irregular nuclear shapes are associated with a variety of human pathologies (reviewed in ref. 13).Here we describe a method to apply forces directly to nuclei in cultured, living, adherent cells. With this method, we estimate a minimum pulling force of a few nanonewtons-far greater than typical intracellular motor forces-is required to significantly displace and deform the nucleus. Although F-actin and microtubules are known to exert mechanical forces on the nuclear surface through molecular motor activity, we show that the intermediate filament networks maintain nuclear mechanical homeostasis. ResultsTo determine the forces that are required for moving and deforming the nucleus, and to identify the cellular components that oppose motion and deformation, we devised a method to ...

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Section: Discussionmentioning

confidence: 99%

Direct force probe reveals the mechanics of nuclear homeostasis in the mammalian cell

Neelam¹,

Chancellor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

126

175

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“…Since Csm4 is the likely KASH protein linking telomeres to cytoskeletal actin in budding yeast Wanat et al 2008;Fridolfsson and Starr 2010), we tested if the csm4D mutation in combination with nup2D would give a synthetic phenotype similar to nup2D ndj1D. First we looked at the sporulation efficiency of the single and double mutants, and found that while 92% of nup2D and 76% of csm4D cells produced two or more spores (n = 200), only 1% of nup2D csm4D double mutant cells (n = 200) produced spores, similar to what we observed for nup2D ndj1D (1.5%, n = 200; Table 1).…”

Section: Dsb Levels Are Elevated In the Absence Of Nup2mentioning

confidence: 99%

The Nucleoporin Nup2 Contains a Meiotic-Autonomous Region that Promotes the Dynamic Chromosome Events of Meiosis

Chu

Gromova²,

Newman³

et al. 2017

Genetics

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Meiosis is a specialized cellular program required to create haploid gametes from diploid parent cells. Homologous chromosomes pair, synapse, and recombine in a dynamic environment that accommodates gross chromosome reorganization and significant chromosome motion, which are critical for normal chromosome segregation. In Saccharomyces cerevisiae, Ndj1 is a meiotic telomere-associated protein required for physically attaching telomeres to proteins embedded in the nuclear envelope. In this study, we identified additional proteins that act at the nuclear periphery from meiotic cell extracts, including Nup2, a nonessential nucleoporin with a known role in tethering interstitial chromosomal loci to the nuclear pore complex. We found that deleting NUP2 affects meiotic progression and spore viability, and gives increased levels of recombination intermediates and products. We identified a previously uncharacterized 125 aa region of Nup2 that is necessary and sufficient for its meiotic function, thus behaving as a meiotic autonomous region (MAR). Nup2-MAR forms distinct foci on spread meiotic chromosomes, with a subset overlapping with Ndj1 foci. Localization of Nup2-MAR to meiotic chromosomes does not require Ndj1, nor does Ndj1 localization require Nup2, suggesting these proteins function in different pathways, and their interaction is weak or indirect. Instead, several severe synthetic phenotypes are associated with the nup2D ndj1D double mutant, including delayed turnover of recombination joint molecules, and a failure to undergo nuclear divisions without also arresting the meiotic program. These data suggest Nup2 and Ndj1 support partially overlapping functions that promote two different levels of meiotic chromosome organization necessary to withstand a dynamic stage of the eukaryotic life cycle.

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“…In unc-84 or unc-83 mutant embryos, the elongation and intercalation of cells proceeds normally, but the nuclei fail to move from their initial positions. 13,15 As the embryo continues to develop, mutant nuclei that fail to migrate are passively pushed toward the dorsal midline by underlying muscle cell migrations and can be observed by DIC microscopy in the dorsal cord of the L1 larva. 15 In the adult hypodermal syncytia, UNC-84 interacts with ANC-1, which interacts with actin to anchor nuclei .…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11] In Caenorhabditis elegans somatic cells, the SUN protein UNC-84 interacts with the KASH protein UNC-83, which recruits microtubule motors kinesin and dynein to facilitate nuclear migration. 12,13 In the early embryo, hypodermal precursors line up in 2 rows across the dorsal midline. As cells intercalate and elongate to form one row of 16 cells, the nuclei migrate contra-laterally to the opposite side of the dorsal midline.…”

Section: Introductionmentioning

confidence: 99%

SUN proteins and nuclear envelope spacing

Cain

Starr

2014

Nucleus

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T he nuclear envelope consists of 2 membranes separated by 30-50 nm, but how the 2 membranes are evenly spaced has been an open question in the field. Nuclear envelope bridges composed of inner nuclear membrane SUN proteins and outer nuclear membrane KASH proteins have been proposed to set and regulate nuclear envelope spacing. We tested this hypothesis directly by examining nuclear envelope spacing in Caenorhabditis elegans animals lacking UNC-84, the sole somatic SUN protein. SUN/ KASH bridges are not required to maintain even nuclear envelope spacing in most tissues. However, UNC-84 is required for even spacing in body wall muscle nuclei. Shortening UNC-84 by 300 amino acids did not narrow the nuclear envelope space. While SUN proteins may play a role in maintaining nuclear envelope spacing in cells experiencing forces, our data suggest they are dispensable in most cells.

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Kinesin-1 and dynein at the nuclear envelope mediate the bidirectional migrations of nuclei

Abstract: The molecular motors kinesin-1 dynein navigate migrating nuclei around cytoplasmic roadblocks.

Cited by 146 publications

References 73 publications

Direct force probe reveals the mechanics of nuclear homeostasis in the mammalian cell

Direct force probe reveals the mechanics of nuclear homeostasis in the mammalian cell

The Nucleoporin Nup2 Contains a Meiotic-Autonomous Region that Promotes the Dynamic Chromosome Events of Meiosis

SUN proteins and nuclear envelope spacing

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