How the architecture of the cerebral cortex develops

Schichtstruktur der Nervenzellen in der Hirnrinde © Charité | Ekaterina Epifanova 

Key processes of early brain development elucidated

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To build up the layered structure of the cerebral cortex, nerve cells migrate to their destination according to a finely regulated pattern. A research team at the Charité – Universitätsmedizin Berlin has now succeeded in tracing the underlying molecular and cellular mechanisms in detail. As now described in the journal Science Advances*, the exact timing of two key processes controlled by the same regulatory protein is crucial. It ensures that nerve cells start their migration at the appropriate moment and then realign themselves in the layer they have reached.

The cerebral cortex – the so-called neocortex – is the outermost area of the brain responsible for cognitive functions such as language, decisions and voluntary motor skills. This is where the nerve cells are precisely arranged: Within the six layers with different functions, the neurons with their branched projections – the dendritic tree – lie exactly parallel to each other. In order to form this layering of the cerebral cortex, nerve cells that have developed from stem cells migrate from their place of origin near the so-called ventricular system to their respective destination. „The structure of the neocortex determines its function. You can imagine the cerebral cortex like a computer chip: Each component has its precise place. A finely tuned sequence of cellular processes is necessary for the nerve cells to reach their final destination. However, if these processes are disturbed, this leads to cognitive impairments and neurological diseases,“ says Dr. Marta Rosário, who, as corresponding last author of the study, has now clarified with her team from the Institute for Cell and Neurobiology at Charité which factors and mechanisms play a role in this.

„We found out that the layer structure is only formed if the newly formed neurons can start their migration to the destination in time. As we were able to show for the first time, they have to organise themselves again after arrival in order to be able to send out their extensions – the dendrites – in the direction of the brain membranes and make contacts,“ says Dr Rosário. „It is only through these two key processes that neurons can align themselves perpendicular to the brain surface and parallel to each other.“ The scientists were able to demonstrate in the mouse model that the regulator protein Zeb2 is responsible for controlling both processes. In order to be able to start their migration at the right moment, the nerve cells must first detach themselves from their original environment, where they are firmly anchored to the surrounding substance – the so-called extracellular matrix. Zeb2 ensures that less of the surface protein neuropilin-1, which is responsible for this anchoring, is produced. In order for the nerve cells to reorient themselves correctly after their arrival in the cerebral cortex, Zeb2 also controls the balance of contacts between the cells by means of another surface protein, cadherin-6. Thus, the regulatory protein reins in two crucial signalling pathways that are responsible for the cells‘ contact with their environment.

Mutations of Zeb2 play an important role in a rare hereditary disease, Mowat-Wilson syndrome, which is associated with defective development and function of the brain and nerves supplying organs. Prof. Dr. Victor Tarabykin, Director of the Institute of Cell and Neurobiology and also the study’s final author, sums up: „With our new findings on the two steps in the development of the cerebral cortex, we now better understand which cell defects could underlie such functional disorders of the brain – but also other neuropsychiatric disorders such as autism or schizophrenia, in which similar maldevelopments occur.“ Dr Rosário’s research team is currently trying to find out what role the interaction of the nerve cells with the so-called extracellular matrix in their environment plays in these steps.

*Epifanova E et al. Adhesion dynamics in the neocortex determine the start of migration and the post-migratory orientation of neurons. Sci Adv 2021 Jul 2;7(27):eabf1973. doi: 10.1126/sciadv.abf1973

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