Institute for the Physics of Living Systems


Size matters

12 August 2019

Recent work from the Goehring Lab, published in Nature Physics, provides evidence cells can use their physical size to decide how to divide.

NG Nature Paper

Throughout our bodies, cells must make decisions about what to do. IPLS scientists have now uncovered that cells can use their size to guide their decision about how to divide.

We all begin as a single cell, which through the process of cell division gives rise to the trillions of cells that make up our bodies. Along the way, cells must decide whether and when to divide and what kind of cell to become.  Cells use a variety of signals to make these decisions.  Recent work from the Goehring Lab, published in Nature Physics, provides evidence cells can use their physical size to decide how to divide.

The team, led by Dr. Nate Goehring (Francis Crick Institute and UCL, Laboratory of Molecular Cell Biology and Institute for Physics of Living Systems), uses the microscopic nematode worm C. elegans to understand how cells in early embryos make decisions to generate an animal.  Their work has focussed on a particular pathway known as PAR polarity, which causes cells to divide asymmetrically to generate two different kinds of cells.  These early asymmetric divisions allow the embryo to create different cell lineages - cells which provide the foundation for the different types of cells and tissues that will make up the adult animal.  However, at some point, cells must stop dividing asymmetrically. 

In earlier research, the team discovered that the PAR polarity pathway generates an asymmetric pattern within the cell through a process called reaction-diffusion. First conceived by the British mathematician Alan Turing, reaction-diffusion is a way to understand how a set of molecules can generate patterns in a cell or tissue simply through their ability to diffuse in space and interact with each other according to certain ‘rules.’  During PAR polarity, two sets of molecules known as PAR proteins self-organize into opposing halves of the cells, separating from each other like oil and water in a process called cell polarization that is critical for the ability of many cells to divide asymmetrically.

For this study, the researchers sought to understand how these asymmetric patterns were affected by the size of cells.  In the early divisions of many animal embryos, cells divide repeatedly without growing and therefore become smaller with each division.  To divide asymmetrically, the pattern of PAR proteins need to ‘fit’ into the cell and therefore would need to be adjusted as cells became smaller.  However, the researchers found that the pattern did not adapt and therefore could only form patterns over a particular range of cell sizes.

“Below a certain cell size, the PAR proteins simply don’t have enough space to segregate and the pattern of PAR proteins collapses” explained Dr. Lars Hubatsch (Francis Crick Institute and UCL, Institute for Physics of Living Systems).

What was particularly interesting was that the size at which their measurements predicted cells could no longer generate PAR polarity coincided roughly with the size at which cells in the C. elegans embryo switch between asymmetric and symmetric divisions.  Therefore, they speculated that this switch could be due to the cells becoming too small to polarize.  To test this hypothesis, they used several tricks to generate small embryos with correspondingly smaller cells.

"We reasoned that if a cell size threshold existed, cells in small embryos would cross this threshold earlier, and therefore we would see a premature switch in how cells divide,” said Dr. Goehring.

And that’s exactly what they saw.  The researchers followed a particular cell lineage known as the germ lineage which is important for generating the reproductive tissues of the adult.  Normally, these cells stop dividing asymmetrically after four divisions. However, in small embryos, cells stopped dividing asymmetrically after only three divisions instead.

"This work nicely highlights how physical limits can guide biological processes and opens the door to thinking about how something as simple and fundamental as size can be used to trigger changes in behavior,” noted Dr. Hubatsch.

Work in the Goehring Lab is provided by core grants from the Francis Crick Institute which is funded by Cancer Research UK, the UK Medical Research Council, and Wellcome Trust and a Marie Skłodowska-Curie grant under the EU Horizon 2020 research and innovation programme.  Dr. Hubatsch was the recipient of a UCL Bogue fellowship.