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On Thursday 7 April, developmental biologist Mike Boxem will deliver his inaugural lecture. In 'A sense of direction - The development of the internal compass of cells', Boxem invites his audience to the molecular world of directional growth in living cells. Boxem's contributions to new technologies make it possible to map the cellular compass. This offers opportunities for research into the development of cancer in epithelial cells.

Mike Boxem investigates at a molecular level how cells become organised along a directional axis. "The body is organised along three axes: top-down, left-right and front-back," he says. "If we look at the smaller levels, we also see direction there: the hairs on your arm all grow in the same orientation. That implies that cells agree on a direction. And if we zoom in even further, to the inside of the cell, it turns out that their organisation is not random either, but is directed by an internal compass. The asymmetric distribution of components and functions guided by this compass is called cell polarity. Its emergence is a fascinating process and a fine example of self-organisation."

One consequence of polarity is asymmetric cell division, which is incredibly important for the development of organisms: this type of division ensures the creation of different types of cells and the correct placement of cells in a tissue. Boxem: "This applies to animals, but as much so to plants. Because in plants, once a cell has been created, it can no longer be moved." In addition, polarity is indispensable for the functioning of cells. "A cell in the intestine, for example, has to place the machinery that takes up nutrients at the top, while a migrating cell has to organise protrusions at the front to ensure movement in the right direction."

By attracting or repelling each other, proteins divide the cell into two opposing domains.

Forming and reading a compass

Boxem works on two fundamental topics related to cell polarity. "Firstly, I am trying to find out how the cell forms its internal compass. We now know that in animals this compass is formed by a series of proteins at the surface of the cell. By attracting or repelling each other, these proteins divide the cell into two opposing domains. What we do not yet fully understand are the molecular principles by which the proteins attract or repel each other."

The second subject that Boxem focuses on is how cells read their compass. Boxem: "A body contains dozens of different types of cells, each with a different shape and organisation to support their function. And all these cells use a compass that largely consists of the same proteins. We still know far too little about the link between the molecular compass and the processes in the cell that ultimately ensure the correct polarised organisation of the cell."

It is hoped that a better understanding of these couplings will also translate into a better understanding of the role of polarity loss in tumours. "Sometimes the polarity of a cell goes wrong. Almost all tumours arise from epithelial cells that have lost their polarity. Such a cell becomes round and loses contact with its neighbours," says Boxem. "An important question is in what ways loss of polarity contributes to the formation of tumours."

Bublin

Boxem's research group already made several important discoveries in the field of cell polarity. For example, using the roundworm Caenorhabditis elegans as a model animal, last year the developmental biologists found a protein that ensures that the intestine of the worm is a nice smooth tube. Without this protein, which has been given the name 'bublin', there is a disruption in the organisation of the top of the cells, causing bubble-shaped bulges in the intestine.

We can now visualise the interaction between proteins that are involved in cell polarity and those that control other processes in the cell.

New technology

Boxem's group also contributed to the development of technology, which in this field of work often quickly leads to new scientific insights. "In 2013, for example, we were among the first groups to enable targeted editing of the C. elegans genome using CRISPR/Cas9." Boxem also makes great use of recent developments such as so-called auxin-induced protein degradation. "This allows you to switch off the function of a protein at the time and in the tissue of your choice. For example, we have been able to show that a protein called NOCA-1 in the skin of C. elegans provides the connection between the cellular compass and the organisation of the microtubules, microscopically small tubes that are part of the cell skeleton."

One technology that Boxem has high hopes for is his adaptation of light-induced clustering for C. elegans in December 2021. "An important goal is to identify interactions between proteins involved in cell polarity and proteins controlling other processes in the cell. Under the influence of fluorescent light, we can now visualise protein clustering, allowing us to demonstrate the existence of protein-protein interactions directly in the worm."