[ad_1]
Summary: Researchers shed light on the genetic underpinnings of social behavior, focusing on the role of the GTF2I gene in Williams syndrome and its contrast in autism spectrum disorders.
The study, which uses human pluripotent stem cells to create brain organoids, reveals that alterations in GTF2I can lead to marked differences in social interaction abilities, evidenced by increased cell death and synaptic defects in organoids lacking this gene.
This discovery not only improves our understanding of variations in social behavior, but also opens the door to potential treatments for the social disabilities associated with autism, offering new hope for improving social functioning. By elucidating the balance of GTF2I expression, the research also contributes to our understanding of evolution and human social cooperation.
Key facts:
- The central role of GTF2I: The GTF2I gene has been identified as a fundamental factor in social behavior, linked to the hypersociability observed in Williams syndrome and in contrast to autism.
- Perspectives of brain organoids: Research using brain organoids has shown that the absence of GTF2I results in significant neuronal development problems, including increased cell death and synaptic defects.
- Potential for treatment development: The findings suggest the possibility of creating treatments that modulate the expression of GTF2I, which could help people with autism improve their social interactions.
Fountain: UCSD
People with Williams syndrome, a neurodevelopmental disorder, have a gregarious “cocktail party” personality, while those with the opposite genetic disorder, in contrast, tend to have autistic traits and are prone to social difficulties.
Now, thanks to new findings from researchers at the Sanford Stem Cell Institute at the University of California, San Diego, scientists better understand why.
The research, published on February 27, 2024 in Cellular reportsIt may help explain variations in human personality and could even lead to the development of a treatment that makes it easier for some people with autism to function better in society.
Williams syndrome, often called “the opposite of autism,” is a rare genetic condition caused by the deletion of approximately 25 genes in the 7q11.23 chromosome region. This alteration produces a constellation of symptoms such as heart disease and developmental delay. He is characterized by a strikingly attractive personality with high sociability, talkativeness, and a vocabulary that masks a typically below-average IQ.
The social strengths of Williams syndrome, however, are a double-edged sword. People with this seemingly paradoxical condition do not meet strangers, making them particularly vulnerable to abuse and bullying.
Instead of a deletion of genes in the 7q11.23 chromosome region, some people’s DNA has a duplication, resulting in behaviors that are, in turn, the complete opposite of those exhibited by people with Williams syndrome. Those with this rare opposite genetic alteration, known as 7q11.23 duplication syndrome, commonly experience symptoms including autism, social phobia, and selective mutism.
While the broader genetic region underlying Williams syndrome has been previously studied, scientists at the University of California, San Diego hypothesized that one gene in particular, GTF2I, is predominantly responsible for the social variation seen in disorder.
“I like to describe this gene as the bias gene,” said Alysson Muotri, PhD director of the Integrated Orbital Space Stem Cell Research Center at the University of California, San Diego and lead author of the paper. “Without it, everyone in the world is your friend.”
To learn more about its role, researchers used human pluripotent stem cells to create mini-organs that mimic the human brain during fetal development, minus GFT2I. At 2 months of age, these so-called brain organoids were smaller than those with GTF2I.
In fact, they found that loss of the gene caused increased cell death, decreased electrical activity, and defects in synapses, the electrochemical connections that allow neurons to communicate with each other.
Researchers still do not fully understand why disruption of the GTF2I gene affects the brain as it does. The team hypothesizes that increased cell death reduces the number of cells in the brain and therefore their electrical activity. It’s also possible that the gene helps repair synapses, meaning that those who don’t have it have more of them that aren’t repaired.
For some with autism, hope for better treatment
Hundreds of genes have been linked to autism, but GTF2I “is the only gene we know of that regulates socialization more directly,” Muotri said. The new research suggests that, when it comes to sociality, the gene is the main player in fetal brain development. In fact, individuals without Williams or 7q11.23 duplication syndrome (i.e., most of us) have a balanced genetic dose of GTF2I and are neither hyper nor hyposocial.
The new study’s findings align with previous work that has demonstrated hypersociality in animals lacking GTF2I. For example, fruit flies that do not have the gene prefer to eat together, without the usually obligatory “social bubble,” and mice that have had the gene removed are friendlier than most.
Additionally, incredibly, alterations in a gene that controls the function of GTF2I (potentially turning it off) may be at least partially responsible for the affectionate and friendly disposition of domesticated dogs compared to wild wolves.
Thanks to Muotri’s team’s findings, there may be hope on the horizon for those with GFT2I-related autism. The research has paved the way for the possible development of a drug that regulates its expression, facilitating the social interaction of affected individuals.
Such treatment may also help those who have a normal GFT2I gene that has been “turned off” by the epigenome, biochemical regulators that modify the way our genes are expressed during development and throughout life.
The team’s work also sheds light on the evolution of human sociality, Muotri maintains. Chimpanzees, the closest evolutionary relative of humans, are social, but only to a point, and prefer to deal with a few chimpanzees at a time. Humans, on the other hand, “create large communities in which we trust each other without really knowing each other,” she said. Case in point: “When you get on a plane, you don’t ask to see the pilot’s license.”
GFT2I is “most likely among the genes that help humans achieve that safe balance, where we trust the community but sometimes we don’t trust others to the same degree,” he added. “There is a fine-tuning of socialization in humans that is not seen in other species.”
The result is the ability to collaborate effectively, and that collaboration, Muotri says, has been key to humanity’s greatest achievements: “When we cooperate we can put a man on the moon. When we cooperate we can decode the human genome. Because we work together.”
Co-authors of the study include Jason W. Adams, Annabelle Vinokur, Janaína S. de Souza, Charles Austria, Bruno S. Guerra, Roberto H. Herai and Karl J. Wahlin, all at UC San Diego.
Money: The study was funded, in part, by the National Institutes of Health (grants R01MH100175, R01NS105969, P01 NICHD033113, MH123828, R01NS123642, R01MH127077, R01ES033636, R21MH128827, R01AG078959, R01DA0 5 6908, R01HD107788, R01HG012351, R21HD109616, R01MH107367 and 5T32GM007198, 1- DP2 -OD006495-01), the United States Department of Defense (W81XWH2110306) and a CARTA grant.
About this research news in social neuroscience, ASD and genetics
Author: Miles Martin
Fountain: UCSD
Contact: Miles Martin – UCSD
Image: Image is credited to Neuroscience News.
Original research: Open access.
“waste of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment”by Alysson Muotri et al. Cellular reports
Abstract
waste of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment
Reflexes
- GTF2I-KO organoids show transcriptomic changes in synaptic function and apoptosis.
- GTF2I-KO neuronal progenitors exhibit higher proliferation rates
- GTF2I-KO neurons have decreased synaptic integrity and increased apoptosis.
- GTF2I-KO organoids have fewer synaptic proteins and decreased electrical activity.
Summary
Individuals with Williams syndrome (WS), a neurodevelopmental disorder caused by hemizygous loss of 26 to 28 genes at 7q11.23, characteristically exhibit a hypersocial phenotype.
Copy number variations and mutations in one of these genes, GTF2I, are associated with altered sociality and are proposed to underlie hypersociality in SW. However, the contribution of GTF2I Human neurodevelopment remains poorly understood.
Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, are differentiated from those edited with CRISPR-Cas9. GTF2I-knock out (GTF2I-KO) pluripotent stem cells to investigate the role of GTF2I in human neurodevelopment. GTF2I-KO progenitors exhibit greater proliferation and cell cycle alterations.
Cortical organoids and neurons demonstrate increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity in a multielectrode array.
Our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.