Summary: A new study has discovered how epigenetic marks and the Cux2 protein influence brain folding. The study reveals that the epigenetic marks H3K27ac and Cux2 are essential for the formation of the gyri and sulci of the cerebral cortex.
These findings improve our understanding of brain development and could inform treatments for brain malformations. Research highlights the complexity of the nervous system and the central role of epigenetics in brain structure.
Highlights:
- The H3K27ac epigenetic mark and the Cux2 protein are crucial for brain folding.
- Cux2 can change brain folding patterns, even in smooth-brained animals.
- The findings offer insight into the treatment of brain malformations linked to folding defects.
Source: UMH
Determining the genetic and epigenetic factors that influence brain folding is the goal of the latest study co-led by the Neurogenesis and Cortical Expansion laboratory, led by researcher Víctor Borrell of the Institute of Neuroscience (IN), a joint center of the Spanish National Research. Council and the Miguel Hernández University (UMH) in Elche, as well as the laboratory led by researcher Vijay K. Tiwari at the Wellcome-Wolfson Institute for Experimental Medicine at Queen’s University in Belfast (UK).
This work, published in the journal Scientists progressshowed that epigenetic marks are a key mechanism in the instructions that give rise to folds in the cerebral cortex and that the Cux2 protein plays a key role in this process.
Borrell’s team had already developed a protomap that establishes at the genetic level where gyri and sulcus will be generated in the brain during a stage of embryonic development in which folds have not yet begun to be generated .
“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 shrink and remain depressed, forming a furrow,” explains the researcher and adds: “This is because there are thousands of genes that are expressed in the cortex of the the embryo during its development. However, they do not express themselves to the same extent in all areas.”
Thanks to the collaboration with Tiwari’s laboratory, an expert in epigenetic and epigenomic analysis, they were able to take this research further and study what is called the epigenetic landscape of cerebral cortex cells:
“We studied much more than a specific gene in a particular location, but we were able to observe all the DNA of cells and their epigenetic modifications, which determine the behavior of these genes, in order to understand the mechanisms that give rise to the DNA of cells. the expression of these genes,” emphasizes Borrell.
To develop this study, the researchers focused on the H3K27ac epigenetic mark, as it is the indicator with the greatest ability to predict gene expression.
However, the results were surprising: “We observed that in many locations where H3K27ac was present, gene expression did not occur and we also observed the opposite case, some genes were expressed without the epigenetic mark being present. present,” explains Lucía del Valle. Antón, co-first author of the article.
Experts agree that this discovery is a clear indicator 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 function in the same way. same way as the rest. body tissues. Without a doubt, there is a long way to study and it is an exciting challenge,” emphasizes Borrell.
This unexpected finding led them to investigate what was happening in genes in which there was a coincidence between the H3K27ac mark and the expression. To do this, they focused on proteins that directly regulate the amount of gene expression: transcription factors. More precisely the Cux2 protein, because its participation in brain development is widely known.
Cux2, a master 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 brain folding and to do so introduced the DNA which codes for this protein into the brain of the embryo during its gestation.
Using this technique, they confirmed that Cux2 is capable of altering folding patterns: “It can generate folds in the otherwise smooth mouse cerebral cortex, and in the case of the ferret, which already has folds, the protein can completely change. the established folding pattern,” explains del Valle Antón.
These results reveal the key role of Cux2 in folding: “We know that for folds to form, multiple processes must occur and, after performing this study, we determined that Cux2 is a master factor that can leverage 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 it possible for wrinkles to form,” explains Borrell.
Using single-cell sequencing, the researchers were able to analyze the changes caused by Cux2 in cells to generate the gyri. They verified that there is a type of radial glial cells, the stem cells responsible for generating neurons, that virtually disappear, allowing other types of radial glial cells to proliferate in greater quantities.
This affects not only the type of progenitor that gives rise to neurons, but also the cell lineage they follow, which in turn is directly involved in the development of gyri and sulci in the brain.
Folding is a feature of the human brain that, when defective, results in 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 fundamental research “is essential to understanding the biology behind these diseases and allows us to be one step closer to finding possible solutions.”
Funding: This work was possible thanks to funding from the European Research Council (ERC) under the Horizon Europe program of the European Union, the Spanish National Research Agency – Spanish Ministry of Science, Innovation and Universities through the Generación de conocimiento, FPI and Juan de la Cierva project programs, the “Severo Ochoa” program for centers of excellence in R&D, the “La Caixa” Foundation, the German Research Society (Deutsche Forschungsgemeinschaft ), the Novo Nordisk Foundation and the Danish National Research Foundation (DNRF).
This research is part of the UNFOLD project ‘Unfolding the Dynamic interaction between Mechanical and Molecular Process in Brain Folding’ (ERC-2023-SyG n°101118729), the objective of which is to study the cortical folding of the view of mechanics, cell biology. , and genetics.
About this news from genetics and epigenetics research
Author: The disadvantages of Angeles
Source: UMH
Contact: Angeles Gallar – UMH
Picture: The image is credited to the UMH-CSIC Neuroscience Institute
Original research: Free access.
“Gene regulatory landscape of cerebral cortex folding” by Víctor Borrell et al. Scientists progress
Abstract
Genetic regulatory landscape of cerebral cortex folding
Folding of the cerebral cortex is a key aspect of mammalian brain development and evolution, and defects are linked to serious neurological disorders.
Primary folding occurs in highly stereotyped patterns predefined in cortical germinal zones by a transcriptomic protomap. The genetic regulatory landscape governing the emergence of this folding protomap remains unknown.
We characterized the spatiotemporal dynamics of gene expression and the active epigenetic landscape (H3K27ac) across prospective folds and fissures in the ferret.
Our results show that the transcriptomic protomap begins to emerge from early embryonic stages and involves cell fate signaling pathways. The H3K27ac landscape reveals restriction of cellular development and engages known developmental regulators, including transcription factor. Cux2.
Manipulate Cux2 expression in cortical progenitors altered their proliferation and folding pattern in ferrets, driven by selective transcriptional changes revealed by single-cell RNA sequencing analyses.
Our results highlight the key relevance of epigenetic mechanisms in defining cerebral cortex folding patterns.