Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

Marzo, Matthew G.; Griswold, Jacqueline M.; Ruff, Kristina M; Buchmeier, Rachel E; Fees, Colby P.; Markus, Steven M.

doi:10.1101/635383

Cited by 5 publications

(4 citation statements)

References 100 publications

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“…We find intermittent increases in velocity, resulting in frequency distributions with long tails (Figure 4h,k). The ranked velocities of SPB‐M and SPB‐D both suggest velocities ranging from 4.5 to 27 nm/s, more comparable to those reported in literature (Marzo et al, 2019; Moore et al, 2009; Omer et al, 2020).…”

Section: Resultssupporting

confidence: 88%

“…In order to estimate the forces driving the movement of the nucleus during mitosis, we follow the mobility of the SPBs that move to the diametrically opposite poles of the nucleus (Knop et al, 1997;Seybold & Schiebel, 2013) comparable to those reported in literature (Marzo et al, 2019;Moore et al, 2009;Omer et al, 2020).…”

Section: In Vivo Spb Motility In Mitotic Cells and Minimal Force Of Pulling The Nucleusmentioning

confidence: 99%

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Collective dynein transport of the nucleus by pulling on astral microtubules during Saccharomyces cerevisiae mitosis

Jain

Khetan

Yadav

et al. 2021

Yeast

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Positioning the nucleus at the bud neck during Saccharomyces cerevisiae mitosis involves pulling forces of cytoplasmic dynein localized in the daughter cell. Although genetic analysis has revealed a complex network positioning the nucleus, quantification of the forces acting on the nucleus and the number of dyneins driving the process has remained difficult. To better understand the collective forces involved in nuclear positioning, we compare a model of dyneins-driven microtubule (MT) pulling, MT pushing, and cytoplasmic drag to experiments. During S. cerevisiae mitosis, MTs interacting with the cortex nucleated by the daughter spindle pole body (SPB) (SPB-D) are longer than the mother SPB (SPB-M), increasing further during spindle elongation in anaphase. Interphasic SPB mobility is effectively diffusive, while the mitotic mobility is directed. By optimizing a computational model of the mobility of the nucleus due to diffusion and MTs pushing at the cell membrane to experiment, we estimate the viscosity governing the drag force on nuclei during positioning. A force balance model of mitotic SPB mobility compared to experimental mobility suggests that even one or two dynein dimers are sufficient to move the nucleus in the bud neck. Using stochastic computer simulations of a budding cell, we find that punctate dynein localization can generate sufficient force to reel in the nucleus to the bud neck. Compared to uniform motor localization, puncta involve fewer motors suggesting a functional role for motor clustering. Stochastic simulations also suggest that a higher number of force generators than predicted by force balance may be required to ensure the robustness of spindle positioning. Take Away• Saccharomyces cerevisiaea cytoplasmic viscosity is estimated by quantifying the in vivo mobility of the nucleus and comparing to simulations.• The in vivo length dynamics of microtubules (MTs) interacting with daughter bud cortex during nuclear positioning in mitosis are measured.• We developed a model of astral MT interactions with cortical dynein in the process of nuclear positioning during mitosis.• A force balance model predicts the minimal force required for nuclear positioning. Kunalika Jain and Neha Khetan contributed equally to the manuscript.

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Section: Resultssupporting

confidence: 88%

Section: In Vivo Spb Motility In Mitotic Cells and Minimal Force Of Pulling The Nucleusmentioning

confidence: 99%

Collective dynein transport of the nucleus by pulling on astral microtubules during Saccharomyces cerevisiae mitosis

Jain

Khetan

Yadav

et al. 2021

Yeast

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“…Spindle tracking was performed on maximum intensity projections (XY) using a custom written MATLAB routine (as described previously 76 ). Dynein-mediated spindle movements were manually selected from the tracking data to obtain the various metrics described in Figures 4B -E, and 5B -E. To determine the fraction of time the spindle centroid resides within 1 µm of the cell cortex ( Figures 4F and 5F), an additional MATLAB routine was generated with which the user manually defines the cell cortex of the mother and bud cell.…”

Section: Spindle Tracking and Statistical Analysismentioning

confidence: 99%

The MAP She1 coordinates directional spindle positioning by spatially restricting dynein activity

Ecklund

Bailey

Kossen

et al. 2021

Preprint

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Dynein motors move the mitotic spindle to the cell division plane in many cell types, including in budding yeast, in which dynein is assisted by numerous factors including the microtubule-associated protein (MAP) She1. Evidence suggests that She1 plays a role in polarizing dynein-mediated spindle movements toward the daughter cell; however, how She1 performs this function is unknown. We find that She1 assists dynein in maintaining the spindle close to the bud neck, such that at anaphase onset the chromosomes are segregated to mother and daughter cells. She1 does so by attenuating the initiation of dynein-mediated spindle movements specifically within the mother cell, ensuring such movements are polarized toward the daughter cell. Our data indicate that this activity relies on She1 binding to the microtubule-bound conformation of the dynein microtubule-binding domain, and to astral microtubules within mother cells. Our findings reveal how an asymmetrically localized MAP directionally tunes dynein activity by attenuating motor activity in a spatially confined manner.

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“…Possible causes of the high incidence of mental disorders in SLE patients include long‐term GCs use, psychological pressure, and recurrent symptoms 15 . Dynein plays a vital role in the development of neurons, such as neuronal migration and neuronal regeneration 16 17 …”

Section: Introductionmentioning

confidence: 99%

Association of DYNC1H1 gene SNP/CNV with disease susceptibility, GCs efficacy, HRQOL, anxiety, and depression in Chinese SLE patients

Huang

Zhang

Wang

et al. 2021

Clinical Laboratory Analysis

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Background Systemic lupus erythematosus is a heterogeneous autoimmune disease characterized by multi‐system injuries and overproduction of autoantibodies. There are many genetic studies on SLE, but no report has considered the relationship between cytoplasmic dynein and SLE susceptibility. Objectives Our study intends to investigate whether DYNC1H1 gene SNP/CNV is related to SLE susceptibility, GCs efficacy, HRQOL, anxiety, and depression in Chinese SLE patients. Methods A total of 502 cases and 544 healthy controls were recruited into the case‐control study, and 472 subjects from the case group were followed up for 12 weeks to evaluate GCs efficacy, HRQOL, anxiety, and depression. Multiplex SNaPshot technique was applied to genotype the seven SNPs of DYNC1H1, and AccuCopyTM method was conducted to quantify the copy number of DYNC1H1. Anxiety and depression were evaluated using HAMA and HAMD‐24 scales, respectively. The SF‐36 scale was used to assess HRQOL. Results The significant association between SNP rs1190606 and SLE susceptibility was displayed in the dominant model (PBH = 0.004) as well as its allele model (PBH = 0.004). We also found that SNP rs2273440 was related to photosensitization symptom in SLE patients (PBH = 0.032). In the follow‐up study, SNP rs11160668 was connected with the improvement of BP in male patients (PBH = 0.011). However, no association of DYNC1H1 gene with GCs efficacy, anxiety, and depression was found. No CNV in DYNC1H1 was detected. Conclusions The study suggests that DYNC1H1 gene polymorphisms may have an effect on SLE susceptibility and BP improvement of HRQOL in Chinese SLE patients.

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Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

Cited by 5 publications

References 100 publications

Collective dynein transport of the nucleus by pulling on astral microtubules during Saccharomyces cerevisiae mitosis

Collective dynein transport of the nucleus by pulling on astral microtubules during Saccharomyces cerevisiae mitosis

The MAP She1 coordinates directional spindle positioning by spatially restricting dynein activity

Association of DYNC1H1 gene SNP/CNV with disease susceptibility, GCs efficacy, HRQOL, anxiety, and depression in Chinese SLE patients

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