Researchers at Baylor College of Medicine and the Duncan Neurological Research Institute at Texas Children's Hospital announced on June 10 that they have identified a set of dysfunctional genes and specific cell types vulnerable to early genetic changes in mouse models of Rett syndrome. The findings, published in Science Advances, may provide new insight into the emergence of symptoms associated with this rare neurological disorder.
Rett syndrome primarily affects girls, who typically develop normally during infancy but begin to lose skills such as speech and intentional movements between 6 and 18 months of age. The disorder is caused by mutations in the MECP2 gene located on the X chromosome. Dr. Ashley Anderson, co-first author and postdoctoral associate in molecular and human genetics, said, "MECP2 gene is on the X chromosome. Female cells have two X chromosomes, but each cell randomly turns off one of these chromosomes, creating a mosaic cellular environment, where about half of the brain cells use the healthy version of MECP2 (MeCP2-positive cells) and the other half use the mutated version (MeCP2-negative cells). However, males only have one X chromosome, so all cells have a mutant MECP2, leading to more severe disease early in life."
Yan Li, co-first author and graduate student in the Zoghbi lab, said studying both female mice with mosaicism and male mice carrying only mutant copies allowed researchers to better understand how healthy and mutant brain cells influence each other: "By studying female mice that mirror this mosaic condition, alongside male mice carrying only the mutant copy, we begin to untangle those effects." The team used bulk RNA sequencing for tissue-wide analysis as well as single-nucleus RNA sequencing for individual cell study. Li said these techniques provided both broad overviews and detailed insights: "Bulk RNA sequencing showed us gene activity across the whole tissue and single-nucleus RNA sequencing allowed us to analyze gene activity in individual cells. Using both techniques let us see the 'big picture' and zoom in on specific cell types."
The study found that significant changes were not evident when analyzing bulk brain tissue from female mice; however, closer examination at a single-cell level revealed important disruptions occurring only within certain cell types: "We found that important changes were not evident in bulk measurements because they occurred only in certain cells," Li said.
Anderson noted that twelve genes consistently altered at very early stages represent an early 'core disease signature.' She added: "Many of these genes are involved in communication between brain cells (synapses), suggesting that disruptions in how neurons connect and signal may be one of the earliest steps in Rett syndrome." The research also indicated even genetically normal brain cells could be affected by their environment due to neighboring defective cells.
Dr. Huda Zoghbi concluded, "Understanding these early and cell-specific changes provides markers to monitor efficacy of interventions and also entry points to understand the brain circuits driving Rett features... If scientists can target the earliest molecular disruptions or protect vulnerable cell types it may be possible to slow or prevent progression." Additional contributors included Guantong Qi, Sih-Rong Wu, Jean-Pierre Revelli, Hu Chen, and Zhandong Liu.
