They reveal a key mechanism for cell division and neural development

Scientists have discovered a mechanism that regulates dynein, a key molecular motor for cell division and neuronal development. The finding may open up new research strategies for diseases caused by problems in development and in neurons.

The research was led by Joan Roig and Núria Gallisà Suñé, both from the Barcelona Institute of Molecular Biology (IBMB), attached to the Higher Council for Scientific Research (CSIC) in Spain, together with Jens Lüders, from the Barcelona Biomedical Research Institute ( IRB Barcelona) and Oscar Llorca, from the Spanish National Cancer Research Center (CNIO).

Dynein is a protein complex essential for life in most eukaryotic organisms. It acts as a motor, transporting the molecules and organelles that are required in different processes and parts of a cell. It does this by moving above microtubules, protein polymers that could be said to be like the highways or highways of cells.

“In animals, a cell without dynein is a non-viable cell”, explains Joan Roig. “Cells need to move and rearrange their internal components to carry out different biological processes, such as dividing. Dynein is one of the central drivers in this and a multitude of other processes,” she adds. In order to carry the different molecules, dynein interacts with dynactin (another protein complex) and with adapters in which it couples the different charges that it must transport. The regulation of these adapters is a central aspect of cell physiology, but very little is still known about them.

Research has revealed how one of these adapters, called BICD2, is activated to bind to dynein, starting it up and thus moving the centrosomes, essential structures in cell division.

Essential mechanism in development

Each time a cell divides, its centrosome doubles, and the resulting two centrosomes move to opposite ends of the cell, from where the two new cells will emerge. For this transport of the centrosomes the intervention of dynein is necessary. The work reveals how BICD2 is activated and put into operation during the initial stages of cell division.

“Our work describes a new regulation mechanism of dynein based on a modification of the adapter through phosphorylation. We explained how the adapter is sequentially phosphorylated by two of the protein kinases, CDK1 and PLK1, which control cell division”, explains Roig. Phosphorylation is a biochemical reaction that regulates numerous molecular processes. As the team has been able to see through electron microscopy and different biochemical techniques, BICD2 exists in a closed conformation, and the modification by phosphorylation causes BICD2 to tend to open, so that it is able to interact with dynein and dynactin, and form an active motor complex.

Until now it was thought that the binding of the charge to the adapter opened the latter, allowing the formation of the active complex and starting the motor, without further intervention of any other process or molecule. The work reveals the importance of phosphorylation as an alternative and, in different cases, an essential mechanism for dynein regulation.

Dynein is involved in the separation of centrosomes (in yellow) during the initial phases of cell division. (Image: Núria Gallisà / Joan Roig / IBMB / CSIC)

New avenues of research

This research not only provides details about an essential mechanism for cell survival, but may open up new research strategies for diseases caused by problems in cell division and in neurons, which in different cases are the result of abnormal function. of dynein and its regulators.

The correct spacing of centrosomes is very important in cell division. When this is not produced properly, Roig details, “daughter cells with an abnormal number of chromosomes (aneuploid) can be produced, a condition that can favor the appearance of cancers, trigger abortions or development problems that result in organ malformations , problems of the central nervous system and other pathologies”.

On the other hand, neurons are highly dependent on the action of dynein, and BICD2 mutations are known to cause spinal muscular atrophy predominantly in the lower extremities (smaled or Kugelberg-Welander syndrome). It is a disease characterized by muscle weakness and atrophy in the legs, due to the loss of motor neurons. Knowing better the regulation of BICD2 can help to better understand this disease and its origin.

The study is titled “BICD2 phosphorylation regulates dynein function and centrosome separation in G2 and M”. And it has been published in the academic journal Nature Communications. (Source: Mercè Fernandez / CSIC)