Rett-causing mutations may stall brain-cell growth in womb: Study
Cell study finds mutation leads fewer immature cells to become mature neurons
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Mutations that cause Rett syndrome may disrupt the growth of brain cells during early development in the womb, according to a study done in cell models.
Scientists found that a Rett-causing mutation, T203M, reduces the number of immature brain cells that develop into mature neurons (nerve cells). The findings shed new light on the biological underpinnings of Rett syndrome, the researchers said.
The study, “MECP2T203M mutation disrupts neurogenesis in human cerebral organoids by altering chromatin dynamics and transcriptional regulation,” was published in Science China Life Sciences.
Rett syndrome is caused mainly by mutations in the MECP2 gene. Rett symptoms include slowed head growth, loss of hand skills, communication difficulties, and behavioral abnormalities.
It’s thought that Rett symptoms occur because the MECP2 gene is required for the normal functioning of healthy neurons in the brain. But research on the role of MECP2 in the brain has focused mainly on how mutations in the gene affect the activity of neurons in the brain after a person is born. The gene is also active during prenatal development, but its role at this early stage has received comparatively little attention in the scientific community.
Lab-grown mini-brains show differences with Rett mutation
A team of scientists in China conducted a series of cell experiments using lab-engineered human stem cells to grow brain organoids, miniature organs grown in dishes as laboratory models. Some of the organoids carried the T203M mutation, while other organoids serving as controls had healthy copies of the gene.
The researchers found that organoids carrying the Rett-causing mutation grew larger than control organoids. Further investigation showed that the Rett organoids had higher counts of immature brain cells, called neural progenitor cells (NPCs), but lower counts of mature neurons.
The MECP2 gene encodes a protein, also called MeCP2, which acts as an activator or repressor of gene activity, helping determine which genes are turned on and off. Rett-causing mutations lead to abnormally low activity of this gene, which can disrupt cells’ genetic activity. In further tests, the researchers found that organoids with the Rett-causing MECP2 mutation showed increased activity of genes that help NPCs grow and multiply, but reduced activity of genes needed for these immature cells to develop into fully functional neurons.
The data suggest that Rett-causing mutations cause immature brain cells to grow when they should be maturing, resulting in too many immature cells and not enough mature neurons.
“[The MECP2 T203M mutation] appears to upregulate genes related to proliferation [cell growth] while downregulating those associated with neuronal differentiation [maturation], leading to an overproliferation of neural progenitors and a reduction in the number of neurons,” the scientists wrote. They noted that additional studies to untangle the molecular mechanisms by which MECP2 mutations lead to this type of dysregulated gene activity “will be very informative.”
