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Title: A systematic genetic screen identifies essential factors involved in nuclear size control}
Article:
Abstract:
Nuclear size correlates with cell size, but the mechanism by which this scaling is achieved is not known. Here we screen fission yeast gene deletion mutants to identify essential factors involved in this process. Our screen has identified 25 essential factors that alter nuclear size, and our analysis has implicated RNA processing and LINC complexes in nuclear size control. This study has revealed lower and more extreme higher nuclear size phenotypes and has identified global cellular processes and specific structural nuclear components important for nuclear size control.
Introduction:
Study of sea urchin embryos led Hertwig more than a century ago to the Kern-Plasma-relation theory, which proposes that the ratio between nuclear size and cell size is constant[1]. A constant ratio between nuclear and cell size has since been reported in many cell types from unicellular yeasts and Tetrahymena to cells of multicellular animals and plants[2–11]. In multicellular organisms, the nucleocytoplasmic ratio varies between cell types, but is generally restricted to a narrow range for cells of each type[10]. There are several lines of evidence that nuclear volume is determined by cell volume, or a factor related to it, and not directly by DNA content. Nuclear volume correlates with cell volume across a wide range of cell sizes in both budding[6] and fission[7] yeasts. In fission yeast, genetic mutations and nutritional states were used to generate cells displaying a 35-fold range of cell volumes; the nuclear volume to cell volume( N/C) ratio was observed to be constant across this range[7]. In small scale pilot experiments, nuclear volume increased steadily with cell volume during the cell cycle, maintaining a constant N/C ratio throughout interphase; no sudden increase in nuclear size accompanied DNA replication in S phase[6, 7]. Gradual nuclear growth during interphase was also observed in HeLa cells[12]. These data indicate that nuclear volume is not directly determined by DNA content. Even a 16-fold increase in DNA content was not sufficient to alter the N/C ratio of fission yeast cells[7]. Furthermore, in situations where DNA content remained constant, nuclear volume responded to changes in cell volume; transfer of the nucleus of a hen erythrocyte into the cytoplasm of a larger HeLa cell resulted in an increase in nuclear volume[13], as did transfer of HeLa cell nuclei into the cytoplasm of a larger Xenopus oocyte[14]. Nuclear volume was observed to increase concomitantly with cell volume following treatment of murine hepatocytes with c-Myc[15], and to scale with cell volume during the reductive divisions of post-16 cell stage C. elegans embryogenesis[9]. However, the mechanism by which cell volume influences nuclear volume has not been established. Studies of centrifuged sea snail embryos and multinucleate yeast cells have demonstrated that diffusible cytoplasmic factors, rather than structural constraints of cell volume, influence nuclear size[5, 7]. Nuclear import of lamins has been implicated in nuclear size control in Xenopus and human cells[8, 16], but yeasts, which lack lamins, also display nuclear scaling[6, 7], so there must be other factors central to nuclear size control. The fission yeast Schizosaccharomyces pombe is genetically tractable, simply shaped and undergoes a closed mitosis, making it a useful system in which to probe the mechanism of nuclear size control in vivo. A screen of non-essential S. pombe gene deletion mutants implicated both bulk nucleocytoplasmic transport and regulation of lipid biosynthesis in nuclear size control[17]. However, no mutants with a low N/C ratio phenotype were identified, leading us to hypothesise that such a phenotype may be sufficiently deleterious to be lethal, and therefore key nuclear size control regulators may be encoded by essential genes[17]. Therefore, to identify novel candidate factors required for the control of nuclear size during interphase, we have carried out a genetic screen of S. pombe essential gene deletion mutants for those exhibiting aberrant N/C ratios. This is the first reported systematic study of the role of products of essential genes in nuclear size control and has uncovered both low N/C ratio and severely aberrant N/C ratio deletion phenotypes.
Discussion:
Here, we describe a systematic genetic screen of S. pombe essential genes for those with deletion mutants that display interphase nuclear size defects and so encode factors that may have roles in nuclear size control. This screen identified 25 potential nuclear size mutants, including 8 with low N/C ratios. This is the first report of mutants displaying low interphase N/C ratios. A previously reported genetic screen of S. pombe non-essential genes identified no low N/C ratios[17]. This essential genes screen also identified mutants with high N/C ratio phenotypes, and mutants with altered nuclear shape. Nuclear size mutants were enriched for genes encoding products with roles in RNA processing, and gene expression more generally. As processing of mRNAs into mRNPs is required for their nuclear export[29], it is possible that perturbed RNA processing could lead to the nuclear accumulation of defective mRNA transcripts, which in turn could lead to N/C ratio alteration by bulk effects analogous to those observed in the previously reported mRNA export defective mutant rae1-167 that displays an enlarged N/C ratio[17]. Alternatively, accumulation of the proteins themselves may influence the N/C ratio; proteins with these functions are often found as part of large complexes comprised of many protein and RNA components. Perturbing the stoichiometry or localisation of a large complex of this kind could influence nucleocytoplasmic transport by affecting the distribution of transport factors between the nucleus and cytoplasm and thus preventing the nucleocytoplasmic transport of other proteins. A further possibility is that altering gene expression or mRNA processing influences expression level of specific RNAs and proteins important for N/C ratio control. In mutants with low N/C ratio, the level of expression of genes encoding proteins required for lipid synthesis may be reduced, limiting nuclear size. Nuclear size mutant gene products were enriched for proteins localised to the nucleus and ribonucleoprotein complexes. The largest group of interactors was a group of spliceosomal proteins suggesting that this ribonucleoprotein complex, or the appropriate regulation of its synthesis or nucleocytoplasmic transport, is important for nuclear size control. Perturbation of mRNA synthesis or mRNA processing will influence the number of ribosomes which could be related to the monitoring of cell size and thus alter the N/C ratio. The strain identified with the lowest N/C ratio was pcm1Δ. Pcm1 forms part of the P-TEFb-methyltransferase complex, another example of a ribonucleoprotein, which is required for 5’ capping of mRNA. Mutants of Cdk9, another component of this complex, also displayed a low N/C ratio suggesting that activity of the P-TEFb-methyltransferase complex is also important for nuclear size control. Both GO enrichment and network analysis implicated the LINC complex and the Nem1-Spo7 phosphatase complex in nuclear size control. The role of the Nem1-Spo7 complex in the regulation of lipid synthesis for nuclear size control has been described previously[17]. LINC complexes are conserved protein complexes that bridge the nuclear envelope, connecting nuclear chromatin to the cytoskeleton[30]. In S. pombe, the KASH domain containing integral outer nuclear membrane protein Kms2 and the SUN domain containing integral inner nuclear membrane protein Sad1 form these bridging complexes[20]. Both kms2Δ and sad1Δ were identified as N/C ratio mutant candidates by genetic screening. It has been suggested that LINC complexes buffer forces on the nuclear envelope preserving nuclear morphology[20], so they may constrain nuclear expansion. This possibility is supported by data from mammalian cells which contain multiple KASH domain containing proteins. Four of them are nesprins consisting of a N-terminal actin binding domain( ABD) separated from a C-terminal transmembrane KASH domain by an extended domain of spectrin repeats, and these are thought to form a filamentous network on the cytoplasmic face of the nuclear envelope[31]. In HaCaT cells, disruption of these interchain interactions by overexpression of the ABD of Nesprin-2 increased nuclear size and expression of reduced length Nesprin-2 decreased nuclear size, demonstrating that the interactions between KASH domain proteins are important for nuclear size control in these cells[31]. Though not the main focus of our study, the screening process also identified deletion mutants with previously unreported nuclear shape defects and asymmetric nuclear division phenotypes. Six mutants with nuclear shape defects were identified; among these were three kinetochore proteins, Ndc80, Spc24 and Mis17, and the LINC complex protein Kms2, supporting a proposed model where LINC complexes buffer inward forces from microtubules on the nuclear envelope[20]. Two mutants were observed to display asymmetric nuclear division, kms2Δ, in which mitotic defects were previously described[20], and a strain carrying a deletion of the gene encoding the nucleoporin Nup107. Mitotic defects have previously been reported in mutants of other components of the Nup107-120 complex, as have defects in Ran nuclear transport[21]; either of these perturbations could lead to asymmetric nuclear division. This genetic screen of fission yeast has uncovered low and more extreme high N/C ratio phenotypes, and revealed novel roles for essential factors in nuclear size control. Bioinformatic analyses have implicated RNA processing and LINC complexes in the control. This suggests that both the regulation of global cellular processes, balancing levels of nucleoplasmic transcription and cytoplasmic translation, and regulation of the levels of specific structural components of the nucleus are important for nuclear size control.
As cells grow and divide , the size of the nucleus is generally maintained as a fixed proportion of cell size . The mechanism by which this nuclear/cytoplasmic ratio is maintained is unclear . Previous studies have suggested that essential gene products may be important for nuclear size control . Therefore , we have exploited the genetic tractability of fission yeast to carry out a systematic genetic screen of deleted essential genes to identify those with aberrant nuclear size phenotypes . Our study has revealed 25 novel genes that influence nuclear size and our bioinformatic analyses have implicated both RNA processing and protein complexes connecting nuclear chromatin to the cytoskeleton in nuclear size control . Our work sheds light on the biological processes that contribute to nuclear size control in fission yeast contributing to our mechanistic understanding of nuclear scaling , a biological phenomenon that is conserved through evolution .