New perspectives on how physical instabilities drive embryonic development: A Cluster of Excellence Physics of Life study

Multicellularity is one of the most profound phenomena in biology, and relies on the ability of a single cell to reorganize itself into a complex organism. It underpins the diversity in the animal kingdom, from insects to frogs, to humans. But how do cells establish and maintain their individuality with such precision? A team led by Jan Brugués at the Cluster of Excellence Physics of Life (PoL) at Dresden University of Technology has uncovered fundamental mechanisms that shed light on this question. The findings, now published in the scientific journal Nature, reveal how cells establish physical boundaries through an inherently unstable process, and how different species have evolved distinct strategies to circumvent this process.

During early development, embryos divide rapidly and with remarkable precision, while reorganizing into many individual units. This requires the cell material (known as cytoplasm) to be partitioned into compartments in a highly orchestrated manner. Researchers in the Brugués group at Physics of Life recently highlighted a new mechanism of cell division in zebrafish, where changes in material properties of the cytoplasm work together with the cytoskeleton to aid division during early development. These early divisions take place over several cell cycles instead of just one, which raises a key question: how does the cytoplasm organize itself so robustly before cell division, without physical boundaries like the cell membrane?

Central to this process are microtubules: filament-like structures that are part of the cell’s internal skeleton. Microtubules assemble into star-shaped formations known as asters, which spread throughout the cell interior to help partition the cytoplasm. Although the process of cytoplasmic partitioning was first described over a century ago, the mechanisms behind compartment formation and their behavior have remained poorly understood. To explore this further, the researchers turned to cytoplasmic extracts from the African clawed frog (Xenopus laevis), which allow key events during development, like the cell cycle or compartment formation, to be studied. These frog egg extracts can spontaneously organize their cytoplasm into compartments that divide over several cell cycles, even when cell membranes are absent. This already suggested that cytoplasmic partitioning was an essential process happening independently of cell division.

Cytoplasmic compartmentalization was inherently unstable in large vertebrate embryos

By combining experiments in the frog extracts with living embryos and theoretical modeling, the researchers discovered that the process of cytoplasmic compartmentalization was inherently unstable in large vertebrate embryos. Microtubule asters didn’t just grow independently; they interacted and sometimes invaded each other, resulting in their fusion instead of remaining separate. “From a physical point of view, this instability should be disrupting embryonic organization,” according to Jan Brugués, the co-corresponding author of the study. “Yet development still proceeds with impressive robustness, meaning embryos must have developed distinct strategies to overcome this instability.”

Timing of cell divisions was precisely matched with the timescale of instability

To explore strategies of stabilizing cytoplasmic partitioning, the authors compared different species. For example, they utilized zebrafish and fruit flies, which share similarly sized embryos, but have different aster structures. Scientists observed that for large asters, such as those from frog extract and zebrafish embryos, the timing of cell divisions was precisely matched with the timescale of instability. Divisions happened quickly enough that asters could spread throughout the embryo without fusing and losing organization. “This close match highlights how highly optimized the cellular machinery is to operate under the extreme conditions of large embryo size and a rapid cell cycle”, said Melissa Rinaldin, first and co-corresponding author of the paper now published in Nature.

Small changes in a physical parameter could explain differences in the development of embryos in varying species

In contrast, species such as the fruit fly possess a reduced rate at which new microtubule asters are built. This results in smaller, more stable asters that gradually fill the cytoplasm over multiple cell divisions. “Our work suggests that even small changes in a physical parameter, like microtubule nucleation or growth, could explain differences in the development of embryos in varying species,” said Jan Brugués. These major changes in the cell architecture all stemmed from small changes in aster structure, due to the differences in the underlying microtubule behavior. These findings suggest that regulation of microtubule nucleation may have acted as an evolutionary ‘dial’, allowing embryos to explore different solutions to patterning in early development, which were key in building multicellular organization.

Findings open new doors to understanding embryonic growth

By identifying simple physical rules that govern cytoplasmic organization, the study provides a new framework for understanding how the first embryonic patterns emerge across the tree of life. With this tightly regulated relationship between physical instability and the cell cycle in different species, this suggests a potentially universal strategy for efficient spatial organization in living systems. These findings open new doors to understanding embryonic growth, with broader implications in evolutionary biology, and human health and disease. Changes in microtubule dynamics that are responsible for self-organization in the cytoplasm could be key in the formation of healthy tissues in the body, and even apply in diseases such as cancer.

Original publication: Melissa Rinaldin, Alison Kickuth, Adam Lamson, Benjamin Dalton, Yitong Xu, Pavel Mejstřík, Stefano Di Talia, Jan Brugués. Robust cytoplasmic partitioning by solving an intrinsic cytoskeletal instability. Nature (2026).
DOI: https://www.nature.com/articles/s41586-025-10023-z

Funding: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC-2068– 390729961- Cluster of Excellence Physics of Life of TU Dresden, Human Frontier Science Program (HFSP), European Molecular Biology Organization (EMBO), European Research Council (ERC), National Institutes of Health (NIH), USA.

About the Cluster of Excellence Physics of Life

Physics of Life (PoL) is one of five Clusters of Excellence at TU Dresden. PoL’s aim is to identify the physical laws underlying the organization of life in molecules, cells, and tissues. Scientists from physics, biology, and computer science come together to investigate how active matter in cells and tissues organizes itself into given structures and gives rise to life. PoL is funded by the DFG within the framework of the Excellence Strategy. It is a cooperation between scientists of the TU Dresden and research institutions of the DRESDEN-concept network, such as the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), the Max Planck Institute for the Physics of Complex Systems (MPI-PKS), the Leibniz Institute of Polymer Research (IPF) and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR). https://physics-of-life.tu-dresden.de/


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