This proposal aims to study how the mitotic membrane network that surrounds the spindle microtubules regulates spindle morphogenesis and spindle orientation. The assembly and maintenance of mitotic spindle morphology requires balancing of forces generated by microtubule-based motor proteins such as dynein and the kinesin Eg5, and proper regulation of microtubule dynamics. Our studies of the lamin-B-containing mitotic membrane network, which we refer to as the lamin-B spindle sheath, have shown that this spindle-associated structure regulates spindle morphology and spindle orientation. Since lamin-B interacts with the dynein regulator NudEL and the microtubule depolymerase MCAK, we hypothesize that the lamin-B spindle sheath that surrounds the body of the spindle microtubules functions as a barrier to limit microtubule growth within the spindle boundary through MCAK and/or NudEL. Moreover, we propose that the lamin-B spindle sheath surrounding the spindle poles regulates the astral microtubules to ensure proper search and capture of the cortical spindle orientation cues. We will test these ideas in Aim 1 and Aim 2 using a number of assays and tools we have generated. We have shown previously that RanGTP, microtubules, and dynein are all required for the lamin-B spindle sheath assembly. More recently, we have found that lamin-B binds to several nucleoporins in mitosis.
In Aim 3, we will test the hypothesis that the interactions between lamin-B and nucleoporins are required for the assembly of the spindle sheath. These studies will make a significant contribution toward understanding how non-microtubule cellular structures regulate spindle assembly and orientation in mitosis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM056312-16
Application #
8727573
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Deatherage, James F
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Carnegie Institution of Washington, D.C.
Department
Type
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20005
Tran, Joseph R; Chen, Haiyang; Zheng, Xiaobin et al. (2016) Lamin in inflammation and aging. Curr Opin Cell Biol 40:124-30
Chen, Haiyang; Zheng, Xiaobin; Xiao, Danqing et al. (2016) Age-associated de-repression of retrotransposons in the Drosophila fat body, its potential cause and consequence. Aging Cell 15:542-52
Tran, Joseph R; Zheng, Xiaobin; Zheng, Yixian (2016) Lamin-B1 contributes to the proper timing of epicardial cell migration and function during embryonic heart development. Mol Biol Cell 27:3956-3963
Jiang, Hao; He, Xiaonan; Feng, Di et al. (2015) RanGTP aids anaphase entry through Ubr5-mediated protein turnover. J Cell Biol 211:7-18
Zheng, Xiaobin; Yue, Sibiao; Chen, Haiyang et al. (2015) Low-Cell-Number Epigenome Profiling Aids the Study of Lens Aging and Hematopoiesis. Cell Rep 13:1505-18
Jiang, Hao; Wang, Shusheng; Huang, Yuejia et al. (2015) Phase transition of spindle-associated protein regulate spindle apparatus assembly. Cell 163:108-22
Oakley, Berl R; Paolillo, Vitoria; Zheng, Yixian (2015) γ-Tubulin complexes in microtubule nucleation and beyond. Mol Biol Cell 26:2957-62
Zheng, Xiaobin; Kim, Youngjo; Zheng, Yixian (2015) Identification of lamin B-regulated chromatin regions based on chromatin landscapes. Mol Biol Cell 26:2685-97
Guo, Yuxuan; Zheng, Yixian (2015) Lamins position the nuclear pores and centrosomes by modulating dynein. Mol Biol Cell 26:3379-89
Wan, Yihan; Zheng, Xiaobin; Chen, Haiyang et al. (2015) Splicing function of mitotic regulators links R-loop-mediated DNA damage to tumor cell killing. J Cell Biol 209:235-46

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