from genes are called messenger RNA (mRNA) variants, and they play a crucial role in the functioning of the brain. Researchers at Weill Cornell Medicine have created an extensive atlas of these mRNA variants in both mouse and human brains, providing a valuable resource for studying brain development and the specialized functions of neurons. This atlas will contribute to a better understanding of the complexities of the brain and its various functions.DNA contains instructions for creating proteins and indicates which genes are functioning in a specific cell. When a gene is transcribed into a raw RNA transcript, it can be modified in various ways to create different splice variants or isoforms. This means that one gene has the potential to produce multiple proteins. Despite the significance of this intricate biological process in understanding various diseases, particularly those affecting the brain, it has been incredibly difficult to study.
In a study published on April 9 in Nature Neuroscience, the scientists employed advanced sequencing techniques to document the mRNA isoforms.The study discovered that there are differences in the genes present in the mouse and human brain. These differences exist in various brain regions, cell types, and growth stages in mice. The researchers also found that even within the same cell type, the variations in gene isoforms can be significant depending on the cell’s location and the brain’s developmental stage.
“This is a significant advancement that will allow us to investigate brain processes in much greater detail,” said Dr. Hagen Tilgner, associate professor of neuroscience at the Center for Neurogenetics of Weill Cornell Medicine’s Feil Family Brain and Mind Research Institute, who is the senior author of the study. Dr. Anoushka Joglekar, the first author of the study, also commented on the results.Dr. Joglekar was a doctoral candidate in the Tilgner lab during the study and was co-mentored by Dr. Elizabeth Ross, Nathan E. Cumming Professor of Neurology and Neuroscience at Weill Cornell Medicine. Dr. Joglekar is currently a postdoctoral researcher at the New York Genome Center, a research institute co-founded by 14 New York academic institutions including Weill Cornell Medicine. Isoform variation is a challenging aspect of biology to understand, often referred to as the “fine print” due to its difficulty to detect using standard RNA-sequencing technology.Differences between mRNA isoforms have posed a challenge for researchers. To tackle this, the team turned to “long read” sequencing, a more costly and time-consuming method that still required extensive data processing for accuracy. They conducted this extensive project by capturing the individual cell and its long read RNA sequences, enabling them to pinpoint isoforms from hundreds of thousands of mouse and human brain cells.
The resulting atlas, based on previous smaller studies by the same team in 2018 and 2021, will serve as a fundamental reference point for future research.Neuroscientists are examining the normal and abnormal functioning and growth of the brain. The initial analysis of the data has uncovered some unexpected findings that will be further explored in future research.
One discovery made by the researchers is that many genes crucial for neuron-to-neuron communication expressed different mRNA isoforms within different regions of the brain. During adolescence, the variation in isoforms was even more pronounced, with many displaying unexpected fluctuation patterns.
Dr. Jog commented, “We observed that some of these isoforms are actively switching on and off throughout development until they stabilize in adulthood.”lekar mentioned that the team observed a significant number of genes with highly variable isoforms that have been associated with major brain disorders such as Alzheimer’s, Parkinson’s, schizophrenia, bipolar disorder, anxiety, and depression in previous genetic studies. Even though most of the findings for mouse and human brain cells were similar, the researchers plan to concentrate on human cells in future studies, particularly comparing isoform variation in normal aging and aging-related brain disorders.
