Size Control of the Nucleus and other Organelles
Cell size varies greatly among different cell types and organisms, and especially during early development when cell division is rapid with little overall growth. A fundamental question is how organelle size is appropriately regulated relative to cell size. Surface to volume ratios differ dramatically depending on cell size, placing variable demands on internal organelles, so proper organelle size regulation is critical to cell function and viability. Models exist to explain size control of linear structures like flagella and stereocilia. However, mechanisms that regulate the size of organelles with more complex geometries have been difficult to elucidate.
The nucleus is one organelle whose size scales during development and between species, while exhibiting size deregulation in many disease states including cancer. Cancer cells with enlarged nuclei almost always represent more aggressive metastatic disease, and nuclear size has long been used by pathologists to stage cancer of the prostate, bladder, breast, and skin. It is largely unknown how nuclear size is regulated and the function of proper nuclear size control.
The long-term goal of my lab’s research is to elucidate mechanisms of nuclear size regulation so as to understand how nuclear size impacts cell and nuclear function and subnuclear organization. As a postdoc in Rebecca Heald’s lab, I showed that nuclear import mediates nuclear scaling between two different size frog species, identified the key proteins involved, and showed that a similar mechanism contributes to nuclear scaling during early frog development. Expanding on this work, my lab uses this same frog system to elucidate how import controls nuclear size and to discover additional mechanisms that account for developmental nuclear scaling.
Complementing biochemical approaches, we are also developing in vivo systems to investigate nuclear size regulation, using tissue culture cells and frog embryos. The general strategy is to determine if nuclear scaling factors identified in vitro also regulate nuclear size in living cells and to explore how specifically altering nuclear size affects cell and subnuclear function. My lab’s research is interdisciplinary in taking both biochemical mechanistic and in vivo functional approaches to understanding nuclear size regulation, and may inform our understanding of nuclear size deregulation in cancer.
In summary, my lab is addressing the fundamental cell biological question of nuclear size regulation. This work could shed light on size control of other organelles and inform how nuclear function becomes deregulated in disease. The long-term significance of this work is to clarify the interplay between nuclear size, subnuclear organization, and cell and nuclear function, and ultimately how breakdowns in these relationships contribute to diseases like cancer.