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Can we prevent aging?
The cell cycle is the mechanism by which cells grow and divide which creates "daughter" cells that go on to enlarge before they also divide into new cells, and so on. The process of cell division includes the enlargement of the nucleus - a cell's genetic control center. The nuceus simultaneously enlarges hand-in-hand with the cell it occupies, before both divide. But, the mechanism involved in this in-tandem enlargement and division is one of the great-unanswered questions of cell biology: what controls this proportional enlargement? What dictates the bigger the cell the bigger the nucleus?
Kazunori Kume PhD of Hiroshima University, Japan, through his research on yeast cells has determined that the nucleus hoards genetic materials, such as mRNAs and proteins, which increases its bulk. He proposes that enlargement of the cell is a result of mRNAs and proteins leaking out of the nuceus and into the cell cytoplasm through the nuclear membrane just before division.
The work is published in PLOS Genetics.
Why use yeast as a model system? Yeast is a single celled organism sharing many characteristics with us, including a cell size similar to human cells. Yeast and humans are both eukaryotes — or organisms that carry genetic material as chromosomes of DNA, within a distinct compartment called a nucleus.
Kume, of HU's Research Center for Healthy Aging, carried out his complex search using the fission-yeast genome in hopes of finding any illusive genes that might affect nucleus size. There are 5000 genes in fission-yeast, 2000 of which are known to be essential to cell growth. Kume decided to search through the other 3000 in hopes of finding some that might also contribute to nucleus size. One-by-one, his team isolated each of these 3000 genes from the fission-yeast genome, and then observed what happened next under the microscope.
In order to determine changes in cell and nuclear size, his team recorded the dimensions of each cell and nucleus missing one particular gene of the 3000 genes under investigation. Having these dimensions, they were able to calculate the cell-to-nucleus ratio of 0.08. This painstaking process gave Kume a point of reference to evaluate cell to nuceus change for the 3000 genes under observation. Thus, his team identified 14 genes whose deletion led to a greater cell-to-nucleus ratio than the newly determined dimension of 0.08.
Further observation also revealed that the usual mechanisms for transporting mRNA from inside the nucleus where it is produced, to inside the cell's cytoplasm where it is required for protein production, were defective.
Analysis of these large and mutated nuclei showed they contain not only a higher concentration of mRNAs but also proteins derived from mRNAs. Swelling of the nucleus disrupted production of lipids which form the double-layered surface of the cell membrane (the lipid bilayer), also adding to the increase in nuclear size.
While this research finally shines a light on cell-to-nucleus ratio changes, Assistant Professor Kume admits there is still more information needed to explain why all this is occurring: "There are so many questions that now need answering, what triggers these membrane changes? Does nuclear expansion cause cancer or result from it? What causes these specific genes to mutate? This research is just the first step into the unknown, It means I now have leads to follow and more mysteries to solve!"
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.
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.
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Fission yeast cells under the microscope. (GREEN) Wild type or normal cells compared
to (BLUE) those having mutated, swollen nuclei. Image Credit: Kazunori Kumi PhD