CRTD: Folding the cerebral cortex at the touch of a button - mechanism of brain folding as in humans decoded

Dresden. A German-Spanish research team has succeeded for the first time not only in increasing the number of nerve cells in a mammalian brain, but also in causing a cortex (cerebral cortex) with very few wrinkles and furrows to develop wrinkles. The scientists led by Dr Federico Calegari from the DFG Research Centre for Regenerative Therapies Dresden - Cluster of Excellence at TU Dresden (CRTD) and Dr Víctor Borrell from the Instituto de Neurociencias de Alicante and the Universidad Miguel Hernández have discovered a mechanism that sets the folding process in motion and also stops it again. The folds and furrows increase the surface area of the brain, which automatically increases the number of nerve cells located there. The results have now been published in "The EMBO Journal" (DOI: 10.1038/emboj.2013.96).

Two years ago, Federico Calegari showed how the potential of reproducible stem cells can be increased in the adult mouse brain. Together with Benedetta Artegiani, the Dresden-based stem cell researcher developed a patented process to specifically accelerate and multiply the division of neural stem cells in the brain. To do this, the scientists increased the special protein complexes CdK4 and cyclinD1. As soon as these proteins were stopped, the stem cells stopped dividing and formed nerve cells.

The shape of the mouse brain differs from that of the human brain. The surface of the human brain has many folds, furrows and fissures, whereas the surface of smaller mammals such as mice tends to be smooth. A folded cortex means a larger surface area in precisely the place in the brain where many neural stem cells and nerve cell precursors are located, which ultimately also increases the number of nerve cells.

Experiments at the CRTD in Dresden showed that although the administration of the special protein complexes during embryonic development of the mice greatly increased the size of the adult brains due to the larger brain mass including the neurons, the cortex did not unfold. How did it come about in the course of evolution that brain folds developed in humans? For example, could a smooth small mammalian brain be manipulated in such a way that it develops folds in which more neuronal stem cells are present than before? This question is occupying researchers worldwide.

In recent years, various research groups have discovered that the cerebral cortex consists of several layers in which different neural precursor cells with different functions are located. In 2010, Wieland Huttner from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden discovered new stem cell types in the outer germinal zone of the brain (subventricular zone). These precursor cells of the further layer maintain contact with the basement membrane on the outer surface of the developing brain via a long, thin cell process. The cells have stem cell properties and can divide repeatedly to produce new nerve cells.

It is precisely this brain layer that is not present in the brains of mice, but is present in ferrets, on which Dr Víctor Borrell from the Instituto de Neurociencias de Alicante and the Universidad Miguel Hernández is conducting research. In contrast to mice, ferrets already have a very slightly folded brain shape. Borrell has now investigated the methods developed in Dresden on ferrets in the published study.

In order to massively increase the expansion of the cortex, Federico Calegari's research group first developed a technique to increase the concentration of the special protein complexes CdK4 and cyclinD1. "Initially, we thought that the cortex of the mouse brain would have to be expanded in width," says the Dresden stem cell researcher, explaining the procedure. However, this proved to be an incorrect working hypothesis. Calegari continues: "We therefore had to achieve a greater longitudinal stretching of the cortex surface in order to achieve the curvature. The experiments on ferrets, which we then carried out together with our Spanish colleagues, showed us that we had found the right approach here."

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Source: Press release of the CRTD/DFG Research Centre for Regenerative Therapies Dresden from 26.4.13