While early brain structures appear to form normally in Rett syndrome, problems emerge later as brain cells grow, move, and begin communicating, according to a new study using lab-grown brain models.
An examination of 3D brain organoids grown from patient-derived stem cells found that certain brain cells matured more slowly during early brain development, while others moved more rapidly and in greater numbers, contributing to overly synchronized and excitable patterns of brain activity — changes that may help explain neurological features seen in Rett syndrome.
“Our findings underscore that [Rett] is not solely a postnatal neurodevelopmental disorder, as MeCP2 deficiency perturbs critical processes already underway in the perinatal period [the period from weeks to weeks after birth],” and “support the possibility that early developmental insights may directly inform therapeutic strategies,” the researchers wrote.
The findings were described in the study, “MeCP2 regulates telencephalic development in human cerebral organoids,” published in Cell Reports.
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How Rett syndrome affects brain development
Rett syndrome is a rare genetic disorder that affects brain development, leading to developmental delays, movement problems, and difficulty with communication. It primarily affects girls. Nearly all cases are caused by mutations in the MECP2 gene, which provides instructions for making the MeCP2 protein, a regulator that helps control the activity of other genes involved in brain development.
Although Rett syndrome symptoms typically appear between 6 and 18 months of age, growing evidence suggests that MeCP2 plays an important role in brain development even before birth.
However, studying exactly how MECP2 mutations affect early brain development is difficult because it would require direct access to developing human brain tissue, which is not feasible for research.
Instead, scientists can use cerebral organoids, sometimes called “mini-brains.” These are three-dimensional structures grown from stem cells that mimic key features of the developing human brain, including its structure, cell types, and gene activity. Because of this, organoids more accurately reflect human brain development than animal models or traditional two-dimensional (2D) cell cultures.
In this study, researchers at the University of California, San Diego, generated cerebral organoids using stem cells derived from people with Rett syndrome and closely examined how brain development unfolded in this model.
The researchers found that early brain development initially proceeded as expected, even without MeCP2. The organoids formed key brain structures, including the neocortex —the part of the brain involved in thinking, learning, and awareness.
Brain cells show abnormal maturation and movement
Nevertheless, MeCP2 was necessary for brain cells to mature and function properly. In Rett organoids, many of the genetic programs that guide the maturation of excitatory neurons, nerve cells that generate electrical signals, were disrupted. As a result, these neurons matured more slowly and showed altered activity patterns.
MeCP2 loss also affected cortical interneurons, a group of brain cells that help regulate overall brain activity. During normal development, these cells migrate to specific locations to help balance brain signaling. Without MeCP2, interneurons showed abnormal migration patterns and increased numbers in certain brain regions.
These changes disrupted the balance of developing brain circuits. In organoids lacking MeCP2, brain cells showed more synchronized and abnormal activity patterns, a phenomenon known as hypersynchrony. This type of altered signaling may help explain neurological features of Rett syndrome, such as abnormal brain activity and seizures, the researchers said.
This study “reinforces the notion that MeCP2 plays critical roles in the prenatal brain and underscores the importance of further investigating its role during early developmental windows,” the researchers wrote.