Background

Cell size is one of the most fundamental characteristics of any cell. It sets the scale for all intracellular structures, such as the mitochondria, spindle, and nucleus. It is particularly remarkable that the nuclear volume always represents a fixed fraction of the cell volume for a given cell type. The constancy of this ratio in nuclear to cellular volume was so striking that researchers in the early 1900s gave it the special name of the karyoplasmic ratio. Yet, the molecular mechanisms through which the nucleus and other intracellular structures sense and respond to cell size remain unknown

Project

Unravelling the mechanisms controlling nuclear size

Here, we aim to identify the molecular mechanisms that couple nuclear volume to cell volume. We will apply an innovative approach combining the expertise of the Skotheim lab in cell size regulation and quantitative live-cell imaging with state-of-the-art technologies for CRISPR/Cas9-mediated genetic screening and image-assisted cell sorting, developed by the Steinmetz lab together with the EMBL Flow Cytometry Core Facility. This approach will enable us to determine the molecular mechanisms that set the nucleus-to-cell volume ratios in animal cells. Identification of such mechanisms will shed light on the century-old fundamental question of how cell volume determines the size of intracellular structures. Additionally, our work will likely provide new insights into stem cell biology. Pluripotent stem cells are typically characterized by their large nuclear size that is crucial for proper gene expression and the maintenance of pluripotent cell states. Therefore, by revealing the molecular pathways that regulate nuclear size, our work will likely inspire novel approaches to facilitating the reprogramming of cells for regenerative medicine.

This project is supported by an Exchange Grant, awarded to Evgeny Zatulovskiy. 

References:

Chan, Y.-H. M. & Marshall, W. F. Scaling properties of cell and organelle size. Organogenesis 6, 88–96 (2010).

Schraivogel, D. et al. High-speed fluorescence image-enabled cell sorting. Science 375, 315–320 (2022).

Tomikawa, J. & Miyamoto, K. Structural alteration of the nucleus for the reprogramming of gene expression. FEBS J 289, 7221–7233 (2022).

Woringer, M., Darzacq, X. & Izeddin, I. Geometry of the nucleus: a perspective on gene expression regulation. Curr Opin Chem Biol 20, 112–119 (2014).

Zatulovskiy, E. & Skotheim, J.M. On the molecular mechanisms regulating animal cell size homeostasis. Trends Genet 36(5), 360–372 (2020).Zatulovskiy, E., Zhang, S., Berenson, D. F., Topacio, B. R. & Skotheim, J. M. Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division. Science369, 466–471 (2020).

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