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Correlation between nuclear and cell size, the nucleocytoplasmic ratio, is a cellular phenomenon that has been reported throughout eukaryotes for more than a century but the mechanisms that achieve it are not well understood. Here, we review work that has shed light on the cellular processes involved in nuclear size control. These studies have implicated nucleocytoplasmic transport, LINC complexes, RNA processing, regulation of nuclear envelope expansion and partitioning of importin α in nuclear size control, moving us closer to a mechanistic understanding of this phenomenon.

The size of the membrane-bound nucleus scales with cell size in a wide range of cell types but the mechanisms determining overall nuclear size remain largely unknown. Here we investigate the role of fission yeast inner nuclear membrane proteins in determining nuclear size, and propose that the Lap2-Emerin-Man1 domain protein Lem2 acts as a barrier to membrane flow between the nucleus and other parts of the cellular membrane system. Lem2 deletion increases membrane flow into and out of the nuclear envelope in response to changes in membrane synthesis and nucleocytoplasmic transport, altering nuclear size. The endoplasmic reticulum protein Lnp1 acts as a secondary barrier to membrane flow, functionally compensating for lack of Lem2. We propose that this is part of the mechanism that maintains nuclear size proportional to cellular membrane content and thus to cell size. Similar regulatory principles may apply to other organelles in the eukaryotic subcellular membrane network., This work was supported by the Francis Crick Institute [www.crick.ac.uk] (to P.N.), which receives its core funding from Cancer Research UK (FC01121), the UK Medical Research Council (FC01121), and the Wellcome Trust (FC01121). This work was also supported by the Wellcome Trust [grant number 093917] [www.wellcome.ac.uk] (to P.N.), JSPS Postdoctoral Fellowships for Research Abroad (to K.K.), JSPS KAKENHI [grants JP26660089 and 17K07756] [http://www.jsps.go.jp/j-grantsinaid/index.html] (to K.K.), JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2902) (to K.K.), the Hiroshima University Education and Research Support Foundation (to K.K.), the Breast Cancer Research Foundation (to P.N.) and The Lord Leonard and Lady Estelle Wolfson Foundation [www.lordandladywolfson.org.uk] (to P.N.)., Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-019-09623-x.

Nuclear size scales with cell size across a wide range of cell types. The mechanism by which this scaling is maintained in growing cells remains unclear. Here we investigate the mechanism of nuclear size homeostasis in the simple eukaryote fission yeast, by monitoring the recovery of aberrant nuclear volume to cell volume (N/C) ratios following perturbation. We demonstrate that both high and low N/C ratios correct rapidly, maintaining nuclear size homeostasis. We assess the kinetics of nuclear and cellular growth and of N/C ratio correction and demonstrate that nuclear and cellular growth rates are not directly coupled. We propose that the mechanism underlying nuclear size homeostasis, involves multiple limiting factors implicated in processes including nucleocytoplasmic transport, lipid biogenesis and RNA processing. We speculate that these link cellular size increases to changes in nuclear contents, which in turn lead to changes in nuclear membrane surface area. Our study reveals that there is rapid nuclear size homeostasis in cells, informing understanding of nuclear size control and size homeostasis of other membrane bound organelles.

How cells control the overall size and growth of membrane-bound organelles is an important unanswered question of cell biology. Fission yeast cells maintain a nuclear size proportional to cellular size, resulting in a constant ratio between nuclear and cellular volumes (N/C ratio). We have conducted a genome-wide visual screen of a fission yeast gene deletion collection for viable mutants altered in their N/C ratio, and have found that defects in both nucleocytoplasmic mRNA transport and lipid synthesis alter the N/C ratio. Perturbing nuclear mRNA export results in accumulation of both mRNA and protein within the nucleus, and leads to an increase in the N/C ratio which is dependent on new membrane synthesis. Disruption of lipid synthesis dysregulates nuclear membrane growth and results in an enlarged N/C ratio. We propose that both properly regulated nucleocytoplasmic transport and nuclear membrane growth are central to the control of nuclear growth and size., Author summary Membrane-bound organelles are maintained at a size proportional to cell size during cell growth and division. How this is achieved is a little-understood area of cell biology. The nucleus is generally present in single copy within a cell and provides a useful model to study overall membrane-bound organelle growth and organelle size homeostasis. Previous mechanistic studies of nuclear size control have been limited to cell-free nuclear assembly systems. Here, we screened a near genome-wide fission yeast gene deletion collection for mutants exhibiting aberrant nuclear size, to identify, more systematically, components involved in nuclear size control. Roles for protein complexes previously implicated in nuclear mRNA export and membrane synthesis were identified. Molecular and genetic analysis of mRNA nuclear export gene mutant cells with enlarged nuclear size revealed that general accumulation of nuclear content, including bulk mRNA and proteins, accompanies the nuclear size increase which is dependent on new membrane synthesis. We propose that properly regulated nucleocytoplasmic transport and nuclear envelope expansion are critical for appropriate nuclear size control in growing cells.