Authors: Kazunori Kume1 and Helena Cantwell2
1: Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Japan
2: Cell Cycle Laboratory, The Francis Crick Institute, London, United Kingdom
Competing Interests: Kazunori Kume and Helena Cantwell are authors of the article discussed in this blog post.
Image Caption: Shown here are the nuclear envelopes of wild-type (cyan) and nuclear size mutant (green) fission yeast cells.
Image Credit: Kazunori Kume, Hiroshima University
The nucleus is a membrane-bound organelle that contains the cell’s chromosomal DNA and is the site of its transcription into mRNA message for translation in the cytoplasm. As it is regularly shaped and generally present in single copy in cells, the nucleus is a useful model for studying membrane-bound organelle growth and organelle size homeostasis. A correlation between nuclear and cell size was first observed in algae and sea urchin embryos over a century ago and has since been reported in a range of cell types and species [1, 2]. Fission and budding yeasts exhibit a constant ratio of nuclear volume to cellular volume (N/C ratio) across a range of cell size mutants and throughout the cell cycle [3, 4]. However, what determines this N/C ratio and how nuclear growth is coupled to cellular growth is unknown.
In our study, featured in PLOS Genetics’ May 2017 issue, we carried out the first genome-wide screen for mutants exhibiting altered N/C ratio to identify novel players involved in N/C ratio determination . We screened a fission yeast gene deletion collection and identified eight gene deletions that led to an interphase N/C ratio increase of at least 15% from the wild type value of 0.08. Intriguingly, among these were two genes encoding components of a protein complex involved in nuclear mRNA export and two encoding components of a complex involved in lipid metabolism, indicating that these processes are both important for N/C ratio control.
Mutation of a gene previously implicated in nuclear mRNA export led to an N/C ratio increase of more than 50%, caused by an increase in nuclear growth rate of twice that required to maintain a wild type N/C ratio. The observed N/C ratio increase required continued RNA and protein synthesis in addition to new membrane synthesis. Molecular and genetic analysis of the mutant cells revealed that the N/C ratio increase was accompanied by non-specific nuclear accumulation of RNA and protein. Deletion of either of the two lipid metabolic genes we identified leads to inappropriate nuclear envelope expansion and an increased N/C ratio. Combining one of these lipid metabolic gene deletions with the nuclear mRNA export mutant leads to an increased N/C ratio greater than that observed in either single mutant, suggesting that two biological processes are independently important for N/C ratio control – nucleocytoplasmic transport and nuclear membrane growth.
Our unbiased genetic screen approach has implicated appropriately regulated nucleocytoplasmic transport and nuclear membrane growth in nuclear size control in growing cells. To fully understand nuclear size control in eukaryotic cells there are still many questions to be answered. How are these two processes coupled to maintain a constant N/C ratio during cell growth? Why does nuclear size have to be carefully controlled? Defects in nuclear size are known to be associated with disease states such as cancer , so do N/C ratio defects contribute to the disease pathology? What are the physiological effects of a misregulated N/C ratio? Our study has made use of a genetically tractable system, fission yeast, to provide novel insights into the biological processes involved in nuclear size control in growing cells; further analysis is required to allow us to fully understand the biological phenomenon of membrane-bound organelle size control.
- Wilson EB. The Karyoplasmic Ratio. In The Cell in Development and Heredity (New York: The Macmillan Company); 1925. pp. 727-733.
- Gregory T. Genome size evolution in animals. In The Evolution of the Genome, T. Gregory, ed. (London: Elsevier Academic Press); 2005. pp. 4-87.
- Jorgensen P, Edgington NP, Schneider BL, Rupes I, Tyers M, and Futcher B. The size of the nucleus increases as yeast cells grow. Mol. Biol. Cell 2007; 18: 3523-3532.
- Neumann FR, and Nurse P. Nuclear size control in fission yeast. J. Cell Biol. 2007; 179: 593-600.
- Kume K, Cantwell H, Neumann FR, Jones AW, Snijders AP, Nurse P (2017) A systematic genomic screen implicates nucleocytoplasmic transport and membrane growth in nuclear size control. PLoS Genet 13(5): e1006767.
- Zink D, Fischer AH, and Nickerson JA. Nuclear structure in cancer cells. Nat Rev Cancer 2004; 9: 677-687.