Fragile X neurons develop atypically in chimeric mice – Spectrum


Brain slice of a mouse brain showing cells carrying the fragile X mutation.

Cell recognizing: A mind slice from a chimeric mouse reveals cells carrying the delicate X mutation (pink) and a typical copy of FMR1 (inexperienced), at one month post-injection.

Neurons derived from the cells of an individual with fragile X syndrome develop atypically when transplanted right into a mouse’s mind, a brand new study has discovered. Among the variations replicate these seen within the brains of individuals with fragile X syndrome.

Researchers have struggled to create mice that precisely mannequin the situation, which stems from mutations within the FMR1 gene. One of many challenges is that mutations in FMR1 behave in a different way in mice: Whereas folks with fragile X syndrome have an FMR1 gene silenced by 200 or extra repeats of a sequence of three amino acids — cytosine, guanine, guanine (CGG) — not even 341 CGG repeats can silence the gene in mice, in keeping with a study printed in ENeuro in August.

Efforts to review fragile X neurons in tradition have additionally been unsuccessful. “The neurons just about keep immature,” rendering them much less helpful for figuring out and testing potential therapies, says research investigator Marine Krzisch, a postdoctoral researcher in Rudolf Jaenisch’s lab on the Whitehead Institute in Cambridge, Massachusetts.

Within the new research, Krzisch and her group mixed in vitro and in vivo approaches, enabling immature human-derived cells to develop contained in the brains of mice. The chimeric mice had been described in Organic Psychiatry in August.

“It’s a really fascinating strategy,” says Lior Brimberg, assistant professor of neuroimmunology on the Feinstein Institutes for Medical Analysis in New York, who was not concerned within the research. However, she says, there’s “nonetheless work to be accomplished.”

Okrzisch and her group reprogrammed induced pluripotent stem cells from an individual with fragile X into neural progenitor cells — immature cells with the potential to turn into many kinds of mind cells. They injected the neural progenitor cells into the brains of immune-deficient new child mice and noticed how these cells matured.

Every mouse acquired 4 injections — all mixtures of fragile X neuronal progenitor cells and management cells, engineered to have purposeful FMR1 genes, within the lateral ventricles. Two fragile X cell traces and two management cell traces had been tagged with pink and inexperienced dyes, respectively.

After 15 days, the injected cells appeared in postmortem mouse brains inside the corpus callosum, a thick band of cells that connects the left and proper hemispheres. After 30 days, the cells had differentiated into neurons and glial cells, a class of assist cells that features astrocytes and microglia, and had traveled to different mind areas, together with the hippocampus, cortex, striatum, thalamus and midbrain.

At first, fragile X progenitor cells matured extra slowly than management cells that wound up in the identical mind areas, an evaluation of their gene expression and morphology confirmed. However after a month, their maturation accelerated. Each cell varieties reached maturity by six months.

The delicate X neurons confirmed elevated expression of genes regarded as markers of synaptic exercise, suggesting that their synapses are hyperexcitable — a discovering that matches what researchers have beforehand noticed in fragile X neurons in vitro.

Although the adjustments in gene expression had been anticipated, one other change got here as a shock, Krzisch says: The form of the delicate X neurons was altered. Usually, the dendrites — small protrusions that reach from a neuron to speak with surrounding cells — are lengthy and skinny within the brains of individuals with fragile X.

“We principally discovered the opposite,” Krzisch says, with the delicate X neurons forming shorter dendrites with bigger, wider heads.

This discovering was “probably the most intriguing” facet of the paper, says Hongbing Wang, professor of physiology at Michigan State College in East Lansing, who was not concerned within the research. “The info is simply reverse to what has been present in animal mannequin and human sufferers.”

The mouse’s personal glial cells surrounded the transplanted cells, which can have contributed to a few of the variations, notes Randi Hagerman, medical director of the MIND Institute on the College of California, Davis, who was not concerned within the work.

“What occurs with the delicate X neuron positively is said to the standing of the astrocytes across the fragile X neuron,” Hagerman says. “And there’s been some research exhibiting that if you happen to combine regular astrocytes with a fragile X neuron, [the neuron] begins to behave regular.”

Krzisch plans to make use of the brand new mannequin to probe the affect of microglia on the morphology and performance of fragile X neurons. “It’s attainable to seek out phenotypes that weren’t beforehand noticed utilizing these fashions,” she says. “We expect that’s a great factor.”


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