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MYT1L mutations associated with autism cause an ‘identity crisis’ in budding brain cells.spectrum

MYT1L mutations associated with autism cause an ‘identity crisis’ in budding brain cells.spectrum

 


The study images show elevated expression of specific genes indicated in pink and green and expected gene expression indicated in blue.

woke up: Genes normally activated in neural stem and progenitor cells (pink and green) in neonatal mice with one (middle) or two (right) non-functional copies of MYT1L compared to controls (left). Expression is up.

Image courtesy: Moritz Mall

Immature neurons with mutations in the autism-associated gene MYT1L fail to repress genes that should only be activated in other cell types. This drawback leads to stalled neuronal maturation and shifts electrical signaling into overdrive. study Published today in molecular psychiatry.

The anticonvulsant drug lamotrigine quells excessive signaling in both human and mouse neurons and reduces hyperactivity in mice with the mutation. MYT1Lresearch also shows.

The results are far from a guarantee that the drug will help people with such mutations, says the chief investigator. Moritz MallGroup Leader of the Hector Institute for Translational Brain Research at DKFZ in Heidelberg, Germany. But it’s starting to become clear how mutations in the gene lead to developmental delay and autism, he says. says.

Fewer than 200 people have been diagnosed MYT1L-related syndromeIt is also characterized by obesity, intellectual disability, and sometimes epilepsy. MYT1L is 1 of 3 genes Necessary for promoting stem cells to become neurons. A 2021 study found that mice with variants in this gene have abnormally small brains and develop immature neurons. first mouse model of the MYT1L mutation.

A new study is the first to look at how gene mutations affect human brain cells.

We show that human and mouse neurons are similarly affected by MYT1L mutations, suggesting that mice are an excellent model to study this gene. Joseph DoughertyAssociate Professor of Genetics and Psychiatry at Washington University in St. Louis, Missouri, and principal investigator of the 2021 study.

“It’s good,” he says. “This means we can test treatments on both.”

M.All and his team created mice with one non-functional copy of MYT1L. (Mice with two mutated copies died shortly after birth.) On day 15 of gestation, the developing cortex of the model embryo had 37% fewer progenitor cells that matured into neurons than control embryos.

At day 18, just before birth, the expression of genes promoting cell division remained elevated in MYT1L embryos, whereas the expression of genes promoting neurogenesis was suppressed.

At birth, the cortex of MYT1L mice was 10% thinner than that of controls.

A mouse brain slice showing the thin cortex of a mouse with the MYT1L variant.

Brain slice: At birth, mice with the MYT1L variant (middle and right) have thinner cortices than controls (left).

In behavioral tests, mice in both juvenile and adult models were hyperactive. Adult male mice, but not females, showed altered social behavior. We did not see the usual tendency to prefer new mice over unfamiliar mice.

Adult model mice show altered expression of genes associated with epilepsy, schizophrenia, and autism, as do neurons derived from human embryonic stem cells with MYT1L variants. Genes that direct cells to muscle and heart tissue, on the other hand, are active in neurons, suggesting an “identity crisis” that delays maturation, Mohr says. “Cells cannot efficiently jump from the progenitor stage to a differentiated neural state.”

Autism-related genes ZNF462 An independent team also represses non-neural genes during neurogenesis reported in January.

H.Human and mouse neurons with MYT1L mutations showed increased spontaneous electrical activity. Mouse cells with only one functional copy increased spiking by an average of 400%.

Among the genes upregulated in both mouse and human neurons was SCN5A, which encodes a sodium channel normally expressed only in the heart. (Related gene SCN2AKnockdown of SCN5A in cells normalized cellular hyperactivity, as did overexpression of MYT1L.

Treatment of cells with lamotrigine, which blocks sodium channels, also sedated excitable cells, and drug-injected MYT1L mice no longer exhibited hyperactivity and anxiety-like behavior.

Survey images: Red paths on black background show excess mouse activity, heatmap-like images show excess mouse neuron activity. Both are sedated with the drug lamotrigine.

Going well: Paths recorded show a mouse lacking MYT1L (upper left) and its neurons (upper right) hyperactive. The drug lamotrigine calms this hyperactivity (lower left and lower right).

Dougherty says it will be important to test lamotrigine in mouse models with different mutations in MYT1L.

According to a 2016 paper, the sodium channel gene SCN10A, which is typically expressed in the peripheral nervous system, is activated in the brain of a mouse model of Pitt-Hopkins syndrome. studySuch misexpression of sodium channel genes may be a “common theme” in rare autism-related conditions, they say. Brady Maher, a principal investigator at the Lieber Institute for Brain Development in Baltimore, Maryland, who led the 2016 study. Maher, who was not involved in the new study, said the mice were “amazing how similar they are.”

Testing lamotrigine in such a genetic model could allow researchers to pool enough participants for trials, Maher says.the medicine was ineffective 2001 small trial Of the 28 children with autism, it may help those with certain genetic conditions.

Lamotrigine is already approved for human use, so Mall said it plans to begin clinical trials in people with MYT1L mutations as early as next year.

“Repurposing is the way to go,” he says. “It could be a very easy achievement.”

Citing this article: https://doi.org/10.53053/QLYF4403

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