Examining the genetical foundation causing Rett Syndrome

In a groundbreaking study, a team led by Kinichi Nakashima at Kyushu University, one of Japan's leading research-oriented institutes, has shed light on the molecular pathology of Rett syndrome. The research, published in the prestigious journal Cell Reports, reveals that the genes MeCP2, miR-199a, and BMP signaling play a significant role in the pathology of this neurodevelopmental disorder.

Rett syndrome, which affects approximately one in every 10,000 to 15,000 female births, is caused by mutations in the gene methyl-CpG binding protein 2, or MeCP2. The study, titled "MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling," delves into the intricate workings of these genes and their impact on the development of the disorder.

The researchers found that a microRNA called miR-199a is associated with MeCP2 and affects the differentiation of neural stem cells, causing an increase in astrocyte production. Astrocytes are support cells in the brain that help maintain everything else while neurons fire off electrical signals. During development, astrocytes and neurons are generated from the same type of stem cells, known as neural stem cells, where their production is carefully controlled. Dysfunction in MeCP2 or miR-199a causes these stem cells to produce more astrocytes than neurons.

The research also identified that miR-199a targets the protein Smad1, a transcription factor critical for proper cellular development. This finding provides a crucial piece of the puzzle, helping to explain why the imbalance between astrocytes and neurons occurs in Rett syndrome.

To further investigate the findings, the team established a brain organoid culture from iPS cells derived from patients with Rett syndrome. When they inhibited BMP, a protein known to play a role in neural development, they were able to reduce the abnormal neural stem cell differentiation observed in Rett syndrome.

The implications of this research are significant. The dysfunction in MeCP2 or miR-199a causes the neural stem cells to generate less neurons and more astrocytes, contributing to the progressive neurodevelopmental symptoms of Rett syndrome. Further investigation is needed to potentially develop clinical treatments for Rett syndrome symptoms based on the team's findings.

The research article can be accessed using the DOI 10.1016/j.celrep.2021.109124. The authors who published the research project on the genetic causation of the neurophysiological disorder Rett syndrome in the journal Cell Reports include Ying Liu, Yan Wang, and colleagues. This study represents a significant step forward in understanding Rett syndrome and could pave the way for future treatments.