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Scaling laws indicate distinct nucleation mechanisms of holes in the nuclear lamina

Nature Physics volume 15, pages 823–829 (2019)Cite this article

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Abstract

During a first-order phase transition, an interfacial layer is formed between the coexisting phases and kinetically limits homogeneous nucleation of the new phase in the original phase. This inhibition is commonly alleviated by the presence of impurities, often of unknown origin, that serve as heterogeneous nucleation sites for the transition. Living systems present a theoretical opportunity: the regulated structure of living systems allows modelling of the impurities, enabling quantitative analysis and comparison between homogeneous and heterogeneous nucleation mechanisms, usually a difficult task. Here, we formulate an analytical model of heterogeneous nucleation of holes in the nuclear lamina, a phenomenon with implications in cancer metastasis, ageing and other diseases. We then present measurements of hole nucleation in the lamina of nuclei migrating through controlled constrictions and fit the experimental data to our heterogeneous nucleation model as well as a homogeneous model. Surprisingly, we find that different mechanisms dominate depending on the density of filaments that comprise the nuclear lamina.

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Fig. 1: Structure and heterogeneities of the nuclear lamina.
Fig. 2: Exclusion of NPCs and lamina from the chromatin-rich bleb.
Fig. 3: Fraction of the blebbed or NE ruptured nuclei \(\varphi\) plotted against the harmonic average of the constriction dimensions r.
Fig. 4: Fit to the experimental data.

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Data availability

Raw data points are plotted in Fig. 3 and are available in other formats from the corresponding author on request.

Code availability

The code that was used to fit the experimental data to the scaling prediction of the heterogeneous nucleation mechanism, and the code that was used to estimate the strain in constrictions of type (3) geometry, are available from the corresponding author on request.

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Acknowledgements

The authors thank E. Bairy, O. Cohen, M. Elbaum, M. King, J. Lammerding, D. Lorber, A. Moriel, S. Nandi, V. Shenoy and K. Wolf for useful comments, and M. Piel for valuable discussions, including about the volume loss of highly deformed nuclei. The authors also thank K. Pannell and E.J. Chen (undergraduates from Rice University and New York University, respectively) for valuable support in the pore etching experiments. The research was supported by Human Frontiers Sciences Program grant RGP0024, National Institutes of Health/National Cancer Institute PSOC award U54 CA193417, National Heart Lung and Blood Institute awards R01 HL124106 and R21 HL128187, NIH fellowship F32 CA228285, the US–Israel Binational Science Foundation, the Israel Science Foundation, a grant from the Katz–Krenter Foundations, a National Science Foundation Materials Science and Engineering Center grant to the University of Pennsylvania, as well as continuing support from the Villalon and Perlman Family Foundations. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other granting agencies.

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Authors and Affiliations

  1. Department of Chemical and Biological Physics, Weizmann Institute of Science, Rehovet, Israel

    Dan Deviri & Samuel A. Safran

  2. Biophysical Engineering Labs, University of Pennsylvania, Philadelphia, PA, USA

    Charlotte R. Pfeifer, Lawrence J. Dooling, Irena L. Ivanovska & Dennis E. Discher

  3. Graduate Group/Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA, USA

    Charlotte R. Pfeifer & Dennis E. Discher

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  1. Dan Deviri
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Contributions

C.R.P. and D.E.D. designed the experiments. D.D. and S.A.S. developed the theory. C.R.P., L.J.D. and I.L.I. performed the experiments and D.E.D. assisted with analysis. D.D. and S.A.S. wrote the paper with important contributions from C.R.P. and D.E.D.

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Correspondence to Dan Deviri.

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Supplementary Information, Supplementary Figures 1–5 and Supplementary References 1–39.

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Deviri, D., Pfeifer, C.R., Dooling, L.J. et al. Scaling laws indicate distinct nucleation mechanisms of holes in the nuclear lamina. Nat. Phys. 15, 823–829 (2019). https://doi.org/10.1038/s41567-019-0506-8

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