April 13, 2024

The genetic secrets of neuron formation

Summary: Researchers have illuminated the fundamental role of the MEIS2 protein in brain development, particularly in the differentiation of inhibitory projection neurons, crucial for movement control and decision-making. This protein, together with DLX5, activates specific genes that guide the development of these neurons.

A mutation in MEIS2, linked to intellectual disabilities in patients, hinders this process, highlighting the importance of the protein in neurodevelopment. The study enriches our understanding of the genetic orchestration behind neuron diversity and highlights the intricate relationship between genetic activation and neuronal fate, offering new insights into the genetic basis of neurodevelopmental disorders.

Key facts:

  1. Critical Function of MEIS2: MEIS2, in collaboration with DLX5, activates genes necessary for the development of inhibitory projection neurons, essential for diverse brain functions.
  2. Consequences of the mutation: A MEIS2 mutation disrupts the formation of these neurons, contributing to the intellectual disabilities seen in affected patients, highlighting the protein’s role in neurodevelopmental disorders.
  3. Complexity of gene regulation: The study sheds light on how MEIS2 interacts with different proteins throughout the body to activate specific sets of genes, illustrating the complex genetic regulation involved in brain development.

Source: Max Planck Institute

Brain development is a highly orchestrated process involving numerous parallel and sequential steps. Many of these steps depend on the activation of specific genes.

A team led by Christian Mayer from the Max Planck Institute for Biological Intelligence discovered that a protein called MEIS2 plays a crucial role in this process: it activates genes necessary for the formation of inhibitory projection neurons.

These neurons are vital for controlling movement and making decisions. A MEIS2 mutation, known in patients with severe intellectual disability, was found to disrupt these processes.

Intrigued by this discovery, the researchers investigated the mechanism by which MEIS2 activates specific genes in projection neurons. Credit: Neuroscience News

The study provides valuable information about brain development and the consequences of genetic mutations.

Nerve cells are an excellent example of intertwined family relationships. The specialized cells that make up the brain come in hundreds of different types, all of which developed from a limited set of generalized progenitor cells – their immature “parents”. During development, only a specific set of genes are activated in a single progenitor cell.

The precise timing and combination of activated genes decide which developmental path the cell will follow. In some cases, seemingly identical precursor cells develop into remarkably different neurons. In others, different precursors give rise to the same type of nerve cell.

The complexity is mind-boggling and not easy to untangle in the laboratory. Yet Christian Mayer and his team decided to do it (Brain Diversity Research). Together with colleagues in Munich and Madrid, they have now added another piece of the puzzle to our understanding of neuron development.

Inhibitory cellular relationships

Scientists studied the formation of inhibitory neurons that produce the neurotransmitter GABA – cells, which are known to display a wide diversity. In the adult brain, inhibitory neurons may act locally or may extend long-range axons to remote brain areas.

Locally connected “interneurons” are an integral part of the cortical circuit, reciprocally linking cortical neurons. Long-range “projection neurons,” on the other hand, primarily populate subcortical regions. They contribute to motivated behavior, reward learning and decision making.

Both types, interneurons and projection neurons, originate in the same area of ​​the developing brain. From here, the newborn neurons migrate to their final locations in the brain.

Using a barcode approach, Christian Mayer and his team tracked the familial relationships between precursor cells and young inhibitory neurons. They found that a protein called MEIS2 plays an important role when a precursor cell “decides” whether to turn into an interneuron or a projection neuron: MEIS2 helps the cellular machinery turn on the genes that are needed for a precursor cell to become become a neuron. projection neuron.

A protein with a far-reaching impact

To advance this development, MEIS2 works together with another protein, known as DLX5. When MEIS2 is absent or does not function correctly, the development of projection neurons stops and a larger fraction of precursor cells develop into interneurons. However, MEIS2 cannot do the job alone.

“Our experiments show that MEIS2 and DLX5 must unite at the same time and in the same cells”, explains Christian Mayer.

“Only the combination of the two will fully activate the genes that drive the development of projection neurons.”

The importance of this process is underscored by previous reports on a MEIS2 variant that was found in patients with intellectual disability and developmental delay. 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 it leads to a failure to induce the specific genes needed to form projection neurons.

“The inability of MEIS2 to activate genes essential for the formation of projection neurons may contribute to neurodevelopmental disorders, such as those observed in patients with mutations in the gene that encodes this protein”, says Christian Mayer.

The complex control by genes

Intrigued by this discovery, the researchers investigated the mechanism by which MEIS2 activates specific genes in projection neurons.

“Patients with MEIS2 mutations suffer from a wide range of effects, such as digit irregularities, impaired lung and brain development, or intellectual disability. At first glance, these symptoms have nothing in common”, reports Christian Mayer.

“This shows how important it is to understand that genes often play very different roles in different parts of the body.”

The genome has millions of non-coding regulatory elements, such as enhancers, promoters and insulators. These elements don’t actually code for proteins themselves, but act like switches, controlling when and where genes are turned on and off.

“Enhancers, which are part of the genome, are like interpreters in the cell. If MEIS2 and DLX5 are present together, a specific set of enhancers becomes active. It is this specific set of enhancers that induces the projection of neuron genes in the brain. In other parts of the body, MEIS2 interacts with other proteins to induce different sets of enhancers”, explains Christian Mayer.

Recent large-scale whole exome sequencing studies in patients have provided a systematic and highly reliable identification of risk genes for neurodevelopmental disorders.

Future studies focusing on the molecular interactions between the proteins encoded by these risk genes, such as MEIS2, will pave the way for a comprehensive understanding of the biological mechanisms underlying neurodevelopmental disorders.

About this genetics and neurodevelopment research news

Author: Marius Bruer
Source: Max Planck Institute
Contact: Marius Bruer – Max Planck Institute
Image: Image is credited to Neuroscience News

Original research: Free access.
“Spatial enhancer activation influences the identity of inhibitory neurons during mouse embryonic development” by Christian Mayer et al. Neuroscience of Nature


Abstract

Spatial enhancer activation influences the identity of inhibitory neurons during mouse embryonic development

The mammalian telencephalon contains distinct types of GABAergic projection neurons and interneurons, originating in the germinal zone of the embryonic basal ganglia. It is unclear how genetic information in the germinal zone determines cell types.

Here we use a combination of in vivo CRISPR perturbation, lineage tracing, and ChIP sequencing analyzes and show that the transcription factor MEIS2 favors projection neuron development by binding enhancer regions in projection neuron-specific genes during mouse embryonic development.

MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity to the appropriate binding sites.

In interneuron precursors, the transcription factor LHX6 represses MEIS2-DLX5-dependent activation of projection neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation.

We propose a differential binding model where the binding of transcription factors in cis-regulatory elements determine differential gene expression programs that regulate cell fate specification in the mouse ganglionic eminence.

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