New EU-funded project provides insight into how the brain develops

The human brain is comprised of billions of different types of cells. These cells are then organized into sophisticated networks, each of which determines a specific function of the brain. But how do the neurons, or nerve cells that form these networks, find the right network? And what happens when they don’t?

To find out, the EU-funded MOMECODE project tracked the generation and migration of neurons in the developing cerebral cortex – the largest part of the brain responsible for much of our thoughts and actions. Using a powerful genetic methodology called MADM (Mosaic Analysis with Double Markers) that provides an unprecedented resolution of a single cell, MOMECODE researchers were able to precisely determine how neural stem cells progressively build up the cerebral.

“For the first time, we quantitatively mapped the output of neural stem cells during the brain’s development,” says MOMECODE researcher Simon Hippenmeyer. “What we discovered was that the proliferation behaviour of neural stem cells is precisely regulated.”

Stem cells and a healthy brain

According to Hippenmeyer, stem cells are characterised by their capacity to differentiate into multiple cell types. During embryonic development, neural stem cells produce the neurons and glia (a connecting tissue) that form the foundation of our nervous system. By tracking the behaviour of these neural stem cells, MOMECODE researchers were able to predict their neuron and glia cell output. “This adds to our understanding of the important role that stem cells play in generating a brain of the correct size,” says Hippenmeyer.

Such insight is key to understanding diseases associated with brain malformation, such as microcephaly (a small brain) and macrocephaly (an oversized brain). “Diseases associated with defects in neural stem cells or the brain’s development put a huge burden on society,” adds Hippenmeyer. “Although still far in the future, we are convinced that the findings emerging from our basic scientific approach will contribute, in one way or the other way, to how we eventually diagnose, prevent and perhaps even treat these diseases.”

Another important finding addresses the ‘nature versus nurture’ question of our brain’s development. In other words, how do genes and other hereditary factors control brain development in a tight interplay with environmental variables? By using sophisticated genetic approaches, MOMECODE researchers looked at both how intrinsic cellular programmes (nature) and the surrounding stem cell niche (nurture) impact neuron output and glia production during the brain’s development. “Unexpectedly, we found a very high degree of environmental factors impacting overall development, which may be relevant to our understanding of brain malformation and neurodevelopmental diseases,” says Hippenmeyer.

More research ahead

With the original research being done on mice, Hippenmeyer and his team are now working to translate their findings to human cells – laying the groundwork for an investigation into the underlying basis of neurodevelopmental disorders.

“During the project, I was in the unique position to contribute to the education of the next generation of molecular life scientists, which I consider to be a privilege and which I greatly appreciate,” says Hippenmeyer.

Rigorously building on the MOMECODE framework, Hippenmeyer and has his team have inaugurated a series of innovative functional genetic studies aimed at determining the underlying molecular and cellular mechanisms of the brain’s development. “We anticipate that these lines of research will contribute to our general understanding of the fundamental genetic mechanisms that control the brain’s development in both health and disease,” he adds.

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