Early Neurons May Stunt Brain Growth in Rare Form of Autism | Spectrum
Mice with a mutated copy of MYT1L, a prominent candidate gene for autism, have unusually small brains and many other physical and behavioral traits mirroring those seen in people with similar mutations, according to a study published today. hui in Neuron.
Mice represent the first model of MYT1L syndrome, a rare genetic disorder marked by autism, intellectual disability, attention deficit hyperactivity disorder (ADHD), obesity and microcephaly, or a head smaller than the average.
“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 influences gene expression. But few studies have explored how mutations in the gene lead to traits seen in people, in part because there are probably fewer than 100 cases worldwide.
Dougherty and his colleagues used CRISPR to design mice with a MYT1L mutation that resembles the one identified in an autistic person. 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 historic work, and it certainly holds promise for exploration in basic science and as a preclinical model,” says Charis Eng, president of Cleveland Clinic’s Genomic Medicine Institute in Ohio, which was not involved in the work.
Physical examinations of the MYT1L mice suggested to the team early on that they were on the right track. Like most people with the mutation, mice are overweight and, like some people with the mutation, have atypically curved fingers. Behavioral tests revealed other similarities.
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 through different generations and through different behavioral tests.”
Multiple tests have suggested that MYT1L mice are less social than wild-type mice: they show a limited degree of interest in other mice and spend less time studying them than controls. In one test, a mouse had to press a button with its nose to open a window in another mouse’s room for a brief chance for interaction. MYT1L mice – and especially males – pressed the button but tended to stay away from the window when it opened.
Animal models do not allow for individual comparisons with humans, says Dougherty. For example, while people with autism may not make frequent eye contact with other people, mouse models of the disease may sniff each other less often or with less enthusiasm than usual.
But given that mice are so different from humans, it’s “encouraging that this model recapitulates much of the phenotype relevant to humans,” Eng says.
The objective of the study of MYT1L mice is to identify which brain functions are altered when MYT1L is mutated, and then to study these circuits in humans.
The new findings open the door to researching therapies that might alleviate some of these traits in people with MYT1L syndrome, Dougherty says. “If you have a good model, you can work to reverse what you see.”
Brain scans showed that MYT1L mice reduced overall brain volume and white matter, the bundles of nerve fibers wrapped in myelin that connect neurons from different regions of the brain.
The mutation speeds up expression of genes involved in brain growth, but dampens the expression of genes that encourage neurons to divide and make more brain cells, according to comparisons of RNA sequencing data from mouse brains embryonic and adult. Many of these deregulated genes are linked to autism and intellectual disability.
Instead of dividing and multiplying, causing brain growth, mouse brain cells tend to mature too early and differentiate early in their final form, cell staining of embryonic mouse brain samples revealed . The result is microcephaly.
However, it’s not entirely clear what populations of neurons are missing in small brains, says Brady Maher, a senior 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 generally missing, but it is also possible that a specific type of neuron is missing.”
Notably, the genes whose expression is altered in MYT1L mice overlap with those that are altered in other mouse models of autism. For example, certain mutations in CHD8, which regulates other genes linked to autism, lead to macrocephaly or a larger than average head.
“We found a very significant overlap between the two,” Chen says. The brain growth genes that CHD8 reveals are rejected in MYT1L mice, and vice versa.
Beyond cell maturation, MYT1L is involved in the normal functioning of myelin in white matter, an important element for neuronal connectivity. Its disruption can lead to some of the neural circuit dysfunctions seen in autism, says Jun Hee Kim, associate professor of cellular and integrative physiology at the University of Texas Health Sciences Center at San Antonio, who has no participated in the study. “This study shows that MYT1L is essential for the early development of neural circuits.”
Dougherty and his colleagues then plan to generate conditional knockout mice – mice missing both copies of MYT1L only in specific regions of the brain – to determine exactly which brain circuits are affected by mutations or loss of the gene.