How genes and epigenetics shape brain folding – Neuroscience News

Summary: A new study revealed how epigenetic marks and the Cux2 protein influence brain folding. The study reveals that the epigenetic marks H3K27ac and Cux2 are key to the formation of the gyri and sulci of the cerebral cortex.

These findings improve our understanding of brain development and may inform treatments for brain malformations. The research underscores the complexity of the nervous system and the key role of epigenetics in brain structure.

Key facts:

1. The H3K27ac epigenetic mark and the Cux2 protein are crucial for brain folding.
2. Cux2 can alter brain folding patterns, even in soft-brained animals.
3. The findings provide insights into the treatment of brain malformations associated with folding defects.

Source: UMH

Determining the genetic and epigenetic factors that influence brain folding is the objective of the latest study co-directed by the Neurogenesis and Cortical Expansion laboratory, directed by researcher Víctor Borrell at the Institute of Neurosciences (IN), a joint Spanish National Research Center. Council and Miguel Hernández University (UMH) of Elche, and the laboratory led by researcher Vijay K. Tiwari at the Wellcome-Wolfson Institute of Experimental Medicine at Queen’s University of Belfast (UK).

This work, published in the journal Advances in sciencehas shown that epigenetic marks are a key mechanism in the instructions that create the folds of the cerebral cortex and that the protein Cux2 plays a defining role in this process.

Borrell’s team had already developed a protomap that determines at the genetic level where the gyri and sulci will be generated in the brain during a stage of embryonic development in which the folds have not yet begun to generate.

“At first, the cortex is smooth, but there is an area that will grow a lot, and as it grows, it will generate a gyrus. Meanwhile, next to it, other areas will grow less and will remain sunken, forming a pit”, explains the researcher and adds: “This is because there are thousands of genes that are expressed in the cortex of the embryo while it is developing . However, they have not been expressed to the same extent in all areas”.

Thanks to the collaboration with the laboratory of Tiwari, an expert in epigenetic and epigenomic analysis, they have been able to take this research a step further and study what is known as the epigenetic landscape of the cells of the cerebral cortex:

“We’ve studied much more than a specific gene in a particular location, but we’ve been able to look at all the DNA from cells and their epigenetic modifications, which determine the behavior of these genes, so we can understand the mechanisms that create the expression of those genes,” Borrell points out.

To develop this study, the researchers focused on the epigenetic mark H3K27ac, as it is the marker with the greatest ability to predict gene expression.

However, the results were surprising: “We observed that in many places where H3K27ac was present, gene expression did not occur, and we also observed the opposite case, there were genes that were expressed without the presence of the epigenetic mark,” says Lucía del Valle. Antón, first co-author of the article.

Experts agree that this discovery is a clear indication of the complexity of the nervous system: “In the field of epigenetics, we find evidence that suggests that the nervous system during its development is an exception and does not work in the same way as the rest. of body tissues. Without a doubt, there is a long way to study and it is an exciting challenge,” Borrell points out.

This unexpected discovery prompted them to investigate what was happening in those genes in which there was a coincidence between the H3K27ac mark and expression. To do this, they focused on proteins that directly regulate how much genes are expressed: transcription factors. Specifically the Cux2 protein, because its involvement in brain development is widely known.

Cux2, a major factor

Cux2 is a protein involved in neuronal differentiation, dendrite growth and the formation of neuronal circuits in general. The experts wanted to verify the influence of this factor on the folding of the brain, and to do this they inserted the DNA that codes for this protein into the brain of the embryo during pregnancy.

Thanks to this technique, they confirmed that Cux2 is capable of changing folding patterns: “It can generate folds in the mouse cerebral cortex, which is otherwise smooth, and in the case of the ferret, which already has folds, the protein can change completely. the established folding pattern,” del Valle Antón explains.

These results reveal the central role of Cux2 in folding: “We know that for folds to form, multiple processes must occur and, after performing this study, we have determined that Cux2 is a key factor that can take advantage of the epigenetic landscape . to make the changes that lead to the expression of thousands of genes that perform different tasks. The combination of all this makes wrinkles possible,” Borrell explains.

Through single-cell sequencing, researchers can analyze the changes Cux2 causes in cells to generate gyri. They verified that there is one type of radial glia cell, the stem cells responsible for generating neurons, that virtually disappears, allowing other types of radial glia cells to proliferate in greater numbers.

This not only affects the type of progenitors the neurons give rise to, but also the cell lineage they follow, which in turn is directly involved in the development of the gyri and sulci in the brain.

Folding is a characteristic of the human brain that, when defective, leads to serious learning and intellectual disabilities. Sometimes, patients have genetic mutations that cause brain malformations due to the absence of gyri. In this regard, Borrell emphasizes that conducting basic research “is essential to understanding the biology behind these diseases and allows us to be a little closer to finding possible solutions.”

Funding: This work has been made possible thanks to funding from the European Research Council (ERC) under the Horizon Europe program of the European Union, the Spanish State Research Agency – the Spanish Ministry of Science, Innovation and Universities through the Generación de conocimiento project programs, FPI and Juan de la Cierva, Severo Ochoa Program for Centers of Excellence in Research and Development, La Caixa Foundation, German Research Society (Deutsche Forschungsgemeinschaft), Novo Nordisk Foundation and the Danish National Research Foundation (DNRF).

This research is part of the UNFOLD project ‘Unfolding the dynamic interplay between mechanical and molecular processes in brain folding’ (ERC-2023-SyG n°101118729), whose objective is to study cortical folding from the viewpoint of mechanics, cell biology. , and genetics.

Related to this genetic and epigenetic research news

Author: Angeles Gallar
Source: UMH
Contact: Angeles Gallar – UMH
Image: Image credited to Instituto de Neurociencias UMH-CSIC

Original research: Open access.
“The regulatory landscape of cerebral cortex folding genes” by Víctor Borrell et al. Advances in science

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ABSTRACT

The gene regulatory landscape of cerebral cortex folding

Folding of the cerebral cortex is a key aspect of mammalian brain development and evolution, and defects are associated with severe neurological disorders.

Primary folding occurs in highly stereotyped patterns that are predetermined in cortical germinal zones by a transcriptomic protomap. The regulatory landscape of genes governing the emergence of this folding protomap remains unknown.

We characterized the spatiotemporal dynamics of gene expression and the active epigenetic landscape (H3K27ac) across future folds and cleavages in ferrets.

Our results show that the transcriptomic protomap begins to emerge at early embryonic stages and involves cell fate signaling pathways. The H3K27ac landscape reveals developmental cell fate restriction and engages known developmental regulators, including transcription factor Cux2.

Manipulating Cux2 expression in cortical progenitors altered their proliferation and folding pattern in unfolding, induced by selective transcriptional changes as revealed by single-cell RNA-sequencing analyses.

Our findings highlight the central importance of epigenetic mechanisms in determining the folding patterns of the cerebral cortex.