2024-03-25 21:58:59
A study shows how proteins convert budding nerve cells into specialized neurons
Brain development is an extremely complex process that involves numerous coordinated steps. What is crucial is the precise activation of certain genes. A team led by Christian Mayer from the Max Planck Institute for Biological Intelligence has now decoded a crucial function of the MEIS2 protein: it activates genes that are necessary for the formation of inhibitory projection neurons. These nerve cells are essential for movement control and decision making. In addition, a MEIS2 mutation, known in patients with severe intellectual disabilities, has been shown to disrupt these processes. The study provides valuable insights into brain development and the consequences of gene mutations.
In the brain, behaviors associated with motivation, rewards, or decisions are enabled by inhibitory projection neurons. The MEIS2 protein plays a crucial role in the correct development of these nerve cells.
© MPI for Biological Intelligence / Julia Kuhl
In the brain, behaviors associated with motivation, rewards, or decisions are enabled by inhibitory projection neurons. The MEIS2 protein plays a crucial role in the correct development of these nerve cells.
© MPI for Biological Intelligence / Julia Kuhl
Neurons are a prime example of intertwined family relationships. The cells that make up the brain come in hundreds of different types, each developing from a limited number of common progenitor cells—their immature “parents.” During development, only a specific set of genes is activated in a single progenitor cell. The exact point in time and the combination of activated genes determine which development path the cell will take. In some cases, seemingly identical progenitor cells develop into strikingly different neurons.
This complexity is not only astonishing, but also not easy to decipher methodologically. Christian Mayer and his team nevertheless attempted this task (diversity research in the brain). Together with colleagues from Munich and Madrid, they have now added another piece of the puzzle to understanding the development of nerve cells.
Inhibitory cell relationships
The scientists examined the formation of inhibitory neurons that produce the neurotransmitter GABA. These cells are known for their great diversity. Such inhibitory nerve cells can be locally networked in the adult brain or can form long-reaching axons to distant brain regions. Locally connected “interneurons” are an essential part of the circuits of the cerebral cortex, where they connect nerve cells to one another. More extensive “projection neurons,” however, are found primarily in subcortical regions of the brain and contribute to behavior related to motivation, reward, and decision-making. Both cell types, interneurons and projection neurons, originate in the same area of the developing brain. From here, the young nerve cells migrate to their final location in the brain.
Using a barcoding approach, Christian Mayer and his team have succeeded in tracing the familial relationships between progenitor cells and young inhibitory neurons. They discovered that a protein called MEIS2 plays an important role in when a progenitor cell “decides” to develop into an interneuron or a projection neuron. This is because MEIS2 supports the cellular machinery in activating the genes that are required for the transformation of a precursor cell into a projection neuron.
A protein with far-reaching effects
To make this transformation possible, MEIS2 works with another protein known as DLX5. If MEIS2 is missing or does not function reliably, the development of projection neurons is stopped and a larger proportion of the precursor cells develop into interneurons instead. However, MEIS2 cannot handle this task alone. “Our experiments have shown that MEIS2 and DLX5 must come together at the same time and in the same cells,” explains Christian Mayer. “Only the combination of the two proteins activates all the necessary genes that control the development of projection neurons.”
The importance of this regulatory process is underscored by reports of a MEIS2 variant documented in patients with intellectual disabilities and delayed development. Due to a small change in the MEIS2 gene, a slightly different protein is produced. Christian Mayer’s team tested this MEIS2 variant in their experiments and found that the genes required for the formation of projection neurons were not activated. “The fact that this MEIS2 variant cannot activate the genes that are crucial for the formation of projection neurons could contribute to the neurodevelopmental disorders observed in patients with mutations in the gene of this protein,” explains Christian Mayer.
The complex control mechanism of genes
Fascinated by this discovery, the researchers turned their attention to the mechanism by which MEIS2 activates the genes required for projection neurons. “Patients with MEIS2 mutations show very different effects, such as irregularities in the toes, impaired lung and brain development or even intellectual disabilities. At first glance, these symptoms have nothing to do with each other,” says Christian Mayer. “This shows how important it is to understand that genes often have very different roles in different parts of the body.”
An organism’s genome has millions of non-coding regulatory elements. These elements do not themselves code for proteins, but rather act like switches that control when and where genes are turned on and off. “So-called enhancers act as interpreters for protein signals in the cell. When MEIS2 and DLX5 come together, certain enhancers are activated. This special group of enhancers in turn activates genes for projection neurons in the brain. In other parts of the body, MEIS2 interacts with other proteins, which leads to the activation of other groups of enhancers,” explains Christian Mayer.
Recently, large-scale sequencing studies have shown that systematic and highly reliable identification of risk genes in neurodevelopmental disorders is possible. Future studies should therefore also focus on the molecular interactions between proteins encoded by risk genes such as MEIS2. This may pave the way for a comprehensive understanding of the biological mechanisms underlying neurodevelopmental disorders.
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