One congenital gene insult is probably the basis for neurodevelopmental disorders

Disease and treatment 21. nov 2021 4 min Assistant professor Navneet A Vasistha Written by Sybille Hildebrandt

The Klf13 gene plays a crucial role in cortical neurons developing correctly. Researchers have come to this conclusion based on computational analysis of mouse genes in different types of brain cells and subsequent behavioural studies of live mice.

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Children born without a functional Klf13 gene may have an increased risk of developing neurodevelopmental disorders. This is the conclusion of a research group from the Biotech Research & Innovation Centre at the University of Copenhagen based on a study that includes both computational analysis of genetic and neurological data from mice and experiments with mice, whose biology in this area is close to that of humans.

“Our study shows that the Klf13 gene appears to be important for proper brain development. Its absence is likely to cause similar defects among people to those in mice, leading to such clinical outcomes as intellectual disability, autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy and schizophrenia later in life,” explains Navneet A. Vasistha, Assistant Professor and co-author of the study led by Konstantin Khodosevich, Associate Professor and Group Leader, Biotech Research & Innovation Centre, University of Copenhagen.

The study aimed to trace when the various genes known to be associated with neurodevelopmental disorders are expressed while the brain’s cortical network develops from the embryonic stage to adulthood. The researchers studied mice diagnosed with the 15q13.3 microdeletion syndrome caused by the lack of at least seven protein-coding genes from chromosome 15 – including Klf13.

Navneet A. Vasistha and colleagues launched the study based on the notion that the Klf13 gene is involved in maturing neural stem cells that turn into cortical neurons. Since the gene usually regulates many other genes, a genetic insult can inhibit or limit the maturation of neural stem cells so that too few cells mature into cortical interneurons, which could explain the association with neurodevelopmental disorders.

“Having this genetic insult indicates that as many as seven genes do not function optimally. The big question then is when and how much each individual genetic insult influences the development of the disorders and whether some of the genetic insults have a definite function in developing the disorders by being the first to be expressed. We mapped this in our study,” says Navneet A. Vasistha.

Analysing data with algorithms

The first part of the study therefore aimed to map when each of these seven genes was expressed in many types of cells during the developmental stages of the mice. This involved both in-depth studies of the mice’s early and late embryonic development and genetic studies of the mice after they were born and until adulthood. By having a complete picture of all stages of development in the form of single-cell gene expression data, the researchers obtained an overview of the time points at which the genes were each expressed in the cells. Due to the complexity of the data, the group used computational tools to systematically study gene expression in different cell types of the brain. This was carried out by Susmita Malwade, lead author of this study. Initially, the researchers mapped how many kinds of cells were present in the large data set. Then they identified the many types of cells that other research groups have described based on marker genes. They could then map the gene expression in the respective types of cells.

“Of the seven genes, Klf13 was the only one to be expressed during the early stages of neurodevelopment. This is a crucial time in brain development because this is when the brain’s neural network is emerging. Klf13 must therefore play a role in the neural network developing properly, and a defect in the gene causes developmental perturbations,” explains Navneet A. Vasistha.

After the algorithm had identified Klf13, the researchers investigated whether such a genetic insult could really trigger neurodevelopmental disorders. Due to the ethical and scientific limitations of studying human fetuses, the researchers instead used genetically modified mice. These studies were based in part on some of the same mouse models that are used to investigate 15q13.3 syndrome and mice that have had the Klf13 gene switched off.

“Our primary mouse model has previously been thoroughly tested and found to be highly representative of the 15q13.3 syndrome. In addition, we also tested the Klf13 knockout mouse and found that it reproduces the features of anxiety present among people with autism spectrum disorders or schizophrenia,” says Navneet A. Vasistha, adding:

Although such animal experiments will always be subject to reservations and we must interpret the data carefully, mouse models are nevertheless an important tool for answering the ethical and scientific questions when studying human brain tissue.

Next step: genetic studies of people

Navneet A. Vasistha says that the study only relates to the influence of one gene on the early stages of neurodevelopment – and not the influence of when and how much other genes and gene combinations have.

“We only investigated one genetic insult, 15q13.3, but several other types of genetic insults are indicated for neurodevelopmental disorders,” explains Navneet A. Vasistha, who says that other research groups can help to clarify many unanswered questions.

“Neurodevelopmental disorders are typically so complex that discerning what kind of genetic insults trigger each disorder is difficult, and our study is only an initial small step. Many research groups need to investigate when the other genes associated with neurodevelopmental disorders are expressed in the cells and how they affect the development of the disorder,” says Navneet A. Vasistha, who says that, according to previous research, most cases of schizophrenia are triggered through interaction between genetic and environmental insults.

“Typically, one gene does not act alone but interacts with many genes. Each of these genetic insults typically has a small effect, but the interaction can amplify this so that the disorder develops. We therefore need to carefully explore the other types of insults and try to find out which ones are most important for the individual disorder,” explains Navneet A. Vasistha, who says that knowing which genes are involved is extremely valuable and that this then offers the hope of developing future methods to restore the function of these genes.

“We cannot say anything about treatment based on this one study, but the study explains in which cells and at what times each gene is expressed. As soon as we know where and when the healthy gene is expressed, determining what happens when a specific gene is deleted is easier,” he says, adding that this knowledge may lead to methods to restore the function of cells where a specific gene is expressed .

“Once we know what is wrong, finding a cure for the insults and thus also for the neurodevelopmental disorders in the form of cell or gene therapies and classical drugs becomes much easier. This kind of analysis enables us to deliver more targeted treatment since people act differently depending on what kind of biological processes are involved. Future research can hopefully clarify genetic insults at the level of the individual and therefore how to treat them optimally in a personalised manner,” explains Navneet A. Vasistha.

In conclusion, he points out that stand-alone studies on mice are not enough. He and his colleagues are already actively investigating the effects of genetic insults among people based on roughly the same procedure: investigating gene expression among people at the embryonic stage and among children and adults by using the same approach as in the mouse study – except based on human data.

Identification of vulnerable interneuron subtypes in 15q13.3 microdeletion syndrome using single-cell transcriptomics” has been published in Biological Psychiatry. In 2021, the Novo Nordisk Foundation awarded a Hallas-Møller Ascending Investigator grant to Konstantin Khodosevich for the project Neuronal Circuits Controlling Psychiatric Disorders. In 2019, the Foundation awarded a BRIDGE fellowship to Navneet A. Vasistha. Co-authors Carmelo Bellardita and Ole Kiehn received funding through a Novo Nordisk Foundation Laureate Research Grant for the project Functional Organisation of Large-scale Integrated Neuronal Networks Controlling Locomotion in Mammals and Mechanisms for Development of Impaired Motor Function in the Diseased Brain.

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