A group of scientists from UCLA and the University of Pennsylvania has discovered 214,516 unique isoforms in the developing neocortex, with more than 70% of them not previously studied. This groundbreaking catalog of gene-isoform variation in the developing human brain offers valuable information about the molecular causes of neurodevelopmental and psychiatric brain disorders, and opens up possibilities for targeted treatments. The findings, published in Science, also explain how transcript expression differs by cell type and maturity.The human brain’s development can be better understood by studying the changes in gene-isoform expression levels. DNA in every cell contains the same genetic information, but it’s the mRNA transcripts that create different proteins, leading to distinct cell functions. These varied proteins, called isoforms, mainly result from alternative splicing, a process highly prevalent in the brain that contributes to its diverse proteins and characteristics. Previous research has shown that regulating isoforms is crucial for understanding brain development and genetics.Dr. Luis de la Torre-Ubieta of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, along with Dr. Michael Gandal, an associate professor of psychiatry and genetics in the Perelman School of Medicine at the University of Pennsylvania, co-led the study. “We determined that genetic factors contribute to the risk for neuropsychiatric disorders,” Dr. de la Torre-Ubieta said.
Prior to this study, the specific role of cell-type-specific splicing and transcript-isoform diversity in the developing human brain had not been thoroughly explored due to limitations in older sequencing technologies. With new third-gene sequencing technologies, the researchers were finally able to investigate this area systematically.The researchers utilized advanced long-read sequencing technologies to capture complete RNA molecules and profile the full-length transcriptome of two main areas of the developing neocortex: the germinal zone, which contains stem cells, and the cortical plate, which houses newly generated neurons.
With this technology, the researchers identified 214,516 unique isoforms, with over 70% of them being previously unstudied. They then compared the two regions of the developing brain and found that changes in isoform expression levels play a crucial role in neurogenesis, differentiation, and cell fate, ultimately contributing to the maturation of the brain.
The study’s findings shed light on the importance of isoform expression in brain development and provide valuable insights for future research in this area.Researchers have discovered numerous isoform switches that take place during brain development, suggesting that previously unidentified RNA-binding proteins play a role in determining cellular identity and fate. Their findings also shed light on the genetic risk factors for neurodevelopmental and neuropsychiatric disorders, prompting a reevaluation of the importance and clinical relevance of numerous rare genetic variants. “We found that genes associated with a high risk of autism or neurodevelopmental disorders are often those that have multiple isoforms, and these isoforms are expressed differently during neurogenesis,” explained dela Torre-Ubieta, an assistant professor of psychiatry and behavioral sciences, stated that the dysregulation of specific isoforms could be a potential mechanism underlying these disorders. Scientists studying the brain frequently use publicly available gene and gene transcript catalogs, but accessing human brain tissue, especially embryonic tissue, is challenging, which limits the comprehensiveness of these datasets. To address this limitation, the researchers obtained six developing human neocortex tissue samples from the mid-gestation period, specifically 15 to 17 weeks post-conception. This developmental time point in human brain is an important period during which the complexity of our brain, the most advanced organ in our body, starts to develop. “These tissue samples allowed for a significant amount of new transcript discovery,” Gandal stated. “And because these databases have not included or represented these crucial time points, we can greatly enhance our knowledge of how genes are controlled in the context of human brain development.” The results of the study have significant therapeutic implications and could be used clinically, the scientists noted. Discovering new transcripts could lead to the identification of new treatments.ment approaches in gene therapy trials or targeted therapeutic trials for individuals with rare mutations associated with psychiatric or neurodevelopmental disorders.
In the short term, the data also has direct implications in improving our ability to make genetic diagnoses of neurodevelopmental disorders. The study revealed thousands of genetic variants that have a greater impact than previously believed, which can help families or individuals carrying those variants better understand the predisposition of their children to certain disorders.
Gandal has shared the dataset with several colleagues at the Children’s Hospital ofPhiladelphia, a city with a large population of children with rare neurodevelopmental disorders or undiagnosed developmental disorders, has physicians who are already using this resource to improve the interpretation of neurogenetics for diagnostic purposes. “I’m really excited to use this resource to help patients,” said Gandal, who is also a practicing psychiatrist. “Having this knowledge brings us one step closer to being able to develop targeted treatments and understand genetic mechanisms in a much more specific way.” Other UCLA authors include Ashok Patowary, Pan Zhang, Celine K. Vuong, Xinzhou Ge, Kangcheng Hou, Minsoo Kim, Michael Mar.golis, Bogdan Pasaniuc, and Jingyi Jessica Li, with contributions from Connor Jops, Naihua Gong, Daniel Vo, Xusheng Wang, and Chunyu Liu, conducted the study. The research received support from the Simons Foundation Autism Research Initiative, the National Institute of Mental Health, the National Science Foundation, and the UCLA Medical Scientist Training Program.
