Advisor(s)
Brittany Lasseigne
Committee Member(s)
Elizabeth Worthey
Haosheng Sun
Jeremy Day
Rita Cowell
Yogesh Dwivedi
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Cell Biology
Date of Award
1-6-2025
Abstract
Molecular phenotype heterogeneity is prevalent across multiple contexts and is mediated by mRNA expression differences and the gene and isoform level. Isoform-level mRNA complexity in the brain is essential for healthy neurodevelopment, and perturbations in AS are associated with many neurological and psychiatric disorders. While previous research has examined how AS changes in the brain, there is still a gap in using newer techniques to study these changes with greater specificity. Therefore, we address this gap by using long-read and scRNA-seq technologies to study isoform-level diversity in AS across four contexts (i.e., disease, sex, region, and cell type) in the mouse brain. We first performed long-read RNA-seq (lrRNA-seq) on the cerebral cortex, cerebellum, hippocampus, and striatum of the mouse brain. We sequenced over 85 million reads and calculated differential gene expression (DGE), transcript expression (DTE), and transcript usage (DTU) across contexts. We found significant DGE, DTE, and DTU across all pairwise brain region comparisons and found the most marked difference in the cerebellum. We also examined DGE, DTE, and DTU within brain regions between sexes, with the most sex differences in the cortex. This was the first work to show the brain region and sex specificity of AS in wild-type mouse brain tissue with lrRNA-seq. Next, we determined if there are cell-type specific alterations in AS between Schinzel-Giedion Syndrome (SGS) patient variant mouse cerebral cortex tissue and controls. We quantified gene and splice junction expression disaggregated by cell barcode and determined cell types. We then compared splice junction usage (SJU) between variant mice and controls and determined that 34 genes had significant changes, where 76% were cell-type-specific. One gene, Son, a splicing cofactor that causes ZTTK syndrome, had shared AS changes between all non-vascular cell types. This is the first work to show neural cell-type-specific AS in a model of SGS and the first to link variants in Setbp1 to AS alterations in Son, emphasizing the importance of AS in another disease context. Together, the results presented in this dissertation underscore the importance of studying AS across contexts, especially in the brain, where AS is highly prevalent.
ProQuest ID
Recommended Citation
Jones, Emma Finn, "Alternative Splicing In The Brain: Across Disease States, Sexes, Regions, And Cell Types" (2025). All ETDs from UAB. 7246.
https://digitalcommons.library.uab.edu/etd-collection/7246
