The “Nucleus Structure and Dynamics” Minisymposium covered topics ranging from the regulation of nuclear morphology, transport, and positioning to nuclear mechanics, rupture, and membrane remodeling.
The first two talks concerned the regulation of nuclear structure. Pan Chen (Levy lab, University of Wyoming) used Xenopus extracts and microfluidics to show that cytoplasmic volume contributes to the regulation of nuclear size, finding that the amount of the histone chaperone nucleoplasmin limits nuclear growth by influencing chromatin organization (Chen et al., 2019). Tina Tootle (University of Iowa) showed that actin localizes to the nucleolus during Drosophila oogenesis and that prostaglandin signaling negatively regulates nuclear actin localization to maintain proper nucleolar structure.
The next two talks dealt with nucleocytoplasmic transport. Saroj Regmi (Dasso lab, NIH) presented new observations from a suite of cell lines with individual nucleoporins (Nups) endogenously tagged for degradation by the auxin-inducible degron system. Loss of individual Nups revealed a modular nuclear pore complex (NPC) architecture, with different domains disassembling somewhat independently of each other and the residual structures retaining a surprising capacity for nuclear transport. Ion Andreu (Roca-Cusachs lab, Institute for Bioengineering of Catalonia) showed that force applied to the nucleus, either manually or through cell growth on stiff substrates, changes the localization of cytoplasmic and nuclear proteins by increasing active nuclear import and export as opposed to passive transport. This mechanism governs the mechanosensitive passage of transcriptional regulators like YAP and TWIST1 through the NPC.
A talk from Hongyan Hao (Starr lab, UC Davis) described a surprising SUN protein–independent function of the KASH protein ANC-1 in Caenorhabditis elegans. SUN and KASH proteins interact in the perinuclear space to form the LINC complex and connect the nucleus to the cytoskeleton to regulate many nuclear processes, including proper nucleus positioning. Hao found that ANC-1 is required to maintain the position of mitochondria, lipid droplets, and other organelles in the cell in addition to the nucleus. As ANC-1 did not localize to these organelles, she proposed that it globally regulates the organization of the cytoskeleton.
Two talks dealt with nuclear membrane rupture. Micronuclei that form around missegregated chromosomes often rupture, contributing to chromosome rearrangements and innate immune activation. Emily Hatch (Fred Hutchinson Cancer Research Center) found that the stability of the micronucleus membrane correlates with micronucleus size and gene density. Her lab is currently investigating how these features correlate with lamina organization in the micronucleus. Tyler Kirby (Lammerding lab, Cornell University) showed that muscular dystrophy–causing lamin A mutations mechanically weaken the nucleus in primary skeletal muscle cells, resulting in transient nuclear ruptures during muscle development that lead to DNA damage and reduced cell viability (Earle et al., 2019). Because DNA damage was found in muscle biopsies from patients carrying these lamin A mutations, he proposed DNA damage as an underlying contributor to pathology in these diseases.
Two talks focused on different aspects of nuclear membrane remodeling. ESCRT proteins are required for nuclear membrane sealing and NPC quality control. Recipient of the Predoctoral Porter Prize for Research Excellence, David Thaller (Lusk lab, Yale School of Medicine) showed that nuclear membrane resealing after loss of nuclear membrane integrity or NPC activity in yeast is initiated by exposure of the inner nuclear membrane protein Heh1 to the cytoplasmic ESCRT protein Chm7. Inhibiting export of Chm7 from the nucleus was sufficient to induce membrane tubulation and herniation, indicating membrane remodeling as a potential mechanism of ESCRT-III–based resealing (Thaller et al., 2019). In the one-cell C. elegans embryo, the maternal and paternal pronuclei must meet before nuclear envelope breakdown and the first mitosis. Mohammad Rahmad (Cohen-Fix lab, NIH) discovered a novel membrane junction, a three-way sheet junction between the nuclear membranes of two fusing pronuclei, which may promote membrane removal during mitosis and proper mixing of the parental genomes (Rahman et al., 2020).
Finally, Megan King (Yale School of Medicine) showed that fission yeast lacking the heterochromatin-binding protein Swi6 show defects in coalescence of heterochromatin foci and increased nuclear deformability, while increasing the amount of heterochromatin stiffens nuclei. She proposed that heterochromatin domains formed by Swi6-dependent liquid–liquid phase separation can do mechanical work that manifests in the mechanical stiffness of nuclei.
Footnotes
Molecular Biology of the Cell Volume 31 Page 397
MBoC is pleased to publish this summary of the Minisymposium on “Nucleus Structure and Dynamics,” held at the 2019 ASCB EMBO Meeting, Washington, D.C., December 10, 2019.
REFERENCES
- Chen P, Tomschik M, Nelson KM, Oakey J, Gatlin JC, Levy DL. (2019). Nucleoplasmin is a limiting component in the scaling of nuclear size with cytoplasmic volume. J Cell Biol , 4063–4078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Earle AJ, Kirby TJ, Fedorchak GR, Isermann P, Patel J, Iruvanti S, Moore SA, Bonne G, Wallrath LL, Lammerding J. (2019). Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells. Nat Mater, 10.1038/s41563-019-0563-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rahman M, Chang IY, Harned A, Maheshwari R, Amoateng K, Narayan K, Cohen-Fix O. (2020). C. elegans pronuclei fuse after fertilization through a novel membrane structure. J Cell Biol , e201909137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thaller DJ, Allegretti M, Borah S, Ronchi P, Beck M, Lusk CP. (2019). An ESCRT-LEM protein surveillance system is poised to directly monitor the nuclear envelope and nuclear transport system. Elife , e45284. [DOI] [PMC free article] [PubMed] [Google Scholar]