Precocious neurons could stunt mind progress in uncommon type of autism | Spectrum
Early maturity: Compared to wild-type mouse neurons (left), those in mice with a mutation in the MYT1L gene (right) mature before they can reproduce, which leads to an above-average brain.
Courtesy of Jiayang Chen, Mary Lambo, Dora Tabachnick / Washington University St. Louis
Mice with a mutated copy of MYT1L, a leading autism candidate gene, have unusually small brains and many other physical and behavioral traits that match those of people with similar mutations, according to a study published today in Neuron.
The mice represent the first model of MYT1L syndrome, a rare genetic disorder characterized by autism, intellectual disability, attention deficit hyperactivity disorder (ADHD), obesity and microcephaly, or a below-average head.
“Generating a mouse line is always a gamble,” says lead researcher Joseph Dougherty, associate professor of genetics and psychiatry at Washington University in St. Louis, Missouri. “The stars have really aligned for us.”
MYT1L codes for a transcription factor, a type of protein that affects gene expression. But few studies have looked at how mutations in the gene lead to the traits seen in humans, in part because there are likely to be fewer than 100 cases worldwide.
Dougherty and colleagues used CRISPR to develop mice with a MYT1L mutation that resembles one identified in an autistic individual. The mice have neurons that mature earlier than expected, which could help explain the traits seen in humans.
As the first mouse model of MYT1L mutations, “This is groundbreaking work and certainly holds great promise for basic research and as a preclinical model,” said Charis Eng, chairman of the Genomic Medicine Institute at Cleveland Clinic, Ohio, not involved in the work.
Physical Similarities:
Physical examinations of the MYT1L mice showed the team early on that they were on the right track. Like most people with the mutation, the mice are overweight and, like some people with the mutation, have atypically crooked fingers. Behavioral tests revealed further similarities.
The mice are also hyperactive, says Jiayang Chen, a doctoral student in Dougherty’s lab who worked on the study. “This is a very robust phenotype that we have seen across generations and various behavioral tests.”
Several tests indicated that the MYT1L mice are less sociable than wild-type mice: they show limited interest in other mice and spend less time studying them than controls. In one test, a mouse had to push its nose into a button to open a window into another mouse’s chamber for a brief opportunity to interact. The MYT1L mice – and the males in particular – pushed the button but tended not to approach the window when it was opened.
Animal models don’t allow one-to-one comparisons with humans, says Dougherty. For example, while autistic people don’t have frequent eye contact with other people, mouse models of the disorder may sniff each other less or less enthusiastically than usual.
But because mice are so different from humans, “it’s encouraging that this model recapitulates much of the phenotype relevant to humans,” says Eng.
The aim of studying the MYT1L mice is to identify which brain functions are changed by the mutation of MYT1L and then to study these circuits in humans.
The new results open the door to exploring therapies that could alleviate some of these traits for people with MYT1L syndrome, says Dougherty. “When you have a good model, you can work on reversing what you see.”
Premature neurons:
Brain scans showed that MYT1L mice reduced total brain volume and white matter, the myelin-sheathed nerve fiber bundles that connect neurons from different brain regions.
The mutation increases the expression of genes involved in brain growth, but attenuates those of genes that stimulate neurons to divide and make more brain cells, according to comparisons of RNA sequencing data from embryonic and adult mouse brains. Many of these dysregulated genes are linked to autism and intellectual disability.
Instead of dividing and multiplying, which causes the brain to grow, the mouse brain cells tend to mature too early and differentiate into their final shape early, as shown by cell staining from mouse embryonic brain samples. The result is microcephaly.
However, it’s not entirely clear what populations of neurons are missing in the smaller brains, says Brady Maher, lead researcher at the Lieber Institute for Brain Development in Baltimore, Maryland, who was not involved in the study. “It could be that all types of neurons are missing in general, but it could also be that a certain neuron type is missing.”
Notably, the genes with altered expression in the MYT1L mice overlap with those that are altered in other mouse models of autism. For example, some mutations in CHD8, which regulates other genes linked to autism, result in macrocephaly or a larger than average head.
“We found a very significant overlap between the two,” says Chen. The brain growth genes that CHD8 evokes are switched off in the MYT1L mice and vice versa.
In addition to cell maturation, MYT1L is involved in the normal function of myelin in white matter, an important element in neural connectivity. Its disruption can lead to some of the neural circuit disorders seen in autism, says Jun Hee Kim, an adjunct professor of cellular and integrative physiology at the University of Texas Health Science Center at San Antonio, who was not involved in the study. “This study shows that MYT1L is critical for the early development of neural circuits.”
Dougherty and his colleagues plan to next create conditional knockout mice – mice that lack both copies of MYT1L only in certain brain regions – to find out exactly which brain circuits are affected by mutations in or loss of the gene.
Quote this article: https://doi.org/10.53053/QFGG4751
