The human brain is a biological masterpiece. One of the powerhouses in this complex architecture comprising billions of neurons is the cerebral cortex, also called the neocortex. This region of the brain, containing the human speech area among other things, has six different layers that run parallel to the surface of the brain. Each layer contains special nerve cells. These populations of neurons differ not only with regard to their circuit patterns – they even have something akin to a position-dependent identity featuring very specific characteristics.
Scientists led by Ulm’s medical scientist Prof Stefan Britsch present new insights into the development of this particular cerebral area in the latest issue of the highly renowned journal NEURON. “So-called neuronal migration plays a key role in this complex process. After all, the cellular migratory movements ensure that neuronal precursor cells find their respective destination in the various layers of the neocortex before they mature there and become integrated in the layer-specific neuronal circuits,” explains Prof Stefan Britsch. Together with his colleague Dr Christoph Wiegreffe, the Head of Ulm University’s Institute for Molecular and Cellular Anatomy has discovered a new molecular mechanism that regulates the development of the neocortex.
In collaboration with cooperation partners from Berlin Charité and scientists from Great Britain and the USA, the researchers at Ulm were able to demonstrate that the transcription factor Bcl11a plays a crucial role in controlling neuronal migration in the neocortex. The researchers at Ulm also managed to prove that the expression of a certain “path-finding protein” (Sema3c) from the group of so-called semaphorins is influenced via this genetic switch. This protein controls the radial migration of neurons. In NEURON, one of the world’s leading journals in the field of neurobiological research owned by Cell Press, the researchers from Ulm demonstrated in a mouse model that the neocortex is much narrower than usual in the forebrain-specific mutation of Bcl11a. They were also able to show that there is then no longer a clear distinction in the layering of the brain. “We were also able to produce evidence that erroneous migratory movements of cortical neurons are associated with impaired neuronal polarity,” adds Dr Christoph Wiegreffe.
Neuronal migration errors lead to neurodevelopmental disorders
Although the findings are the result of protracted basic research, they are of considerable clinical significance. For example, mutations of Bcl11a were recently detected in humans for the first time, mutations that are associated with cerebral maldevelopment. This leads to a delay in speech development and intellectual maturation in affected individuals. So-called autism spectrum disorders are also attributed to subtle errors in neuronal migration. “In this connection, the migratory behaviour of neocortical neurons play a role, as well as the associated cellular ‘identity problems’ and circuit disorders,” the brain researchers state.
Incidentally, the scientists’ research enables them to gain fascinating insight into neuronal migratory processes. Using live cell imaging, a method enabling live cells to be observed in their natural environment, the team of researchers was even able to film the migratory movements of single neurons. In addition to classic conditional gene knockout strategies in the mouse (loss-of-function approach), the scientists also used so-called gain-of-function approaches to suppress certain phenotypes of the mutation, enabling them to characterise the function of specific genes in the brain better. The study involved the use of a wide variety of methods, from molecular biological and immunohistochemical methods to imaging techniques such as confocal microscopy and live cell imaging.
Consequently, the scientists at Ulm were not only able to prove that the mutation-related migratory and polarity defects were due in part to the Bcl11a mediated increased expression of Sema3c. They also succeeded in inhibiting the occurrence of migratory defects in brain development by normalising the axonal path-finding protein.
Britsch and Wiegreffe are convinced that: “Armed with these new findings on neuronal migration, we were able to clarify fundamental issues concerning brain development and to gain a better understanding of how disorders of the brain and nervous system develop.” The project was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG) and Ulm University’s Medical Faculty within the modular programme for young scientists.
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