A Representative Role for the Alternative Splicing of Synaptic Genes
Abstract/Contents
- Abstract
- Alternative splicing enables the differential expression of multiple mRNA transcripts and multiple functionally unique protein isoforms derived from the same gene. Interestingly, genes encoding synaptic regulators are both alternatively spliced and implicated in the development of several neuropsychiatric disorders including autism spectrum disorders, schizophrenia, and Tourette’s syndrome. Mechanisms by which synapses are formed and dynamically regulated remain unclear, but the alternative splicing of trans-synaptic regulators is thought to play a decisive role in mediating neuronal communication. To deduce a representative model for neuronal alternative splicing in the making and shaping of synapses (as reflected in changes to synaptic RNA and protein levels), Khdrbs (Sam68, Slm1, Slm2) and Nova splice factors (Nova1, Nova2) were virally overexpressed in primary neurons cultured from neonatal mice. In-vitro validation of RNA-seq-reported changes in synaptic splicing demonstrated that Khdrbs factors exclusively regulate the alternative splicing of multiple Neurexin (Nrxn) homologs, cell-adhesion molecules crucial for the development of functional synapses. Additionally, immunoblot analysis revealed a strikingly consistent loss of key synaptic proteins, coupled with decreased expression of astrocytic markers, in Slm1-overexpressed cultures, suggesting a splice factor-specific role in maintaining tripartite synapses by which glial contributions are likely paramount. In short, the experiments performed here capture the discrete effects of neuronal alternative splicing in the regulation of core synaptic components and offer insight into the molecular bases underpinning a broad range of animal behaviors.
Description
| Type of resource | text |
|---|---|
| Publication date | May 4, 2023 |
Creators/Contributors
| Author | Choeb, Reyan |
|---|---|
| Thesis advisor | Südhof, Thomas |
| Thesis advisor | McConnell, Susan |
| Degree granting institution | Stanford University, Department of Biology |
Subjects
| Subject | alternative splicing |
|---|---|
| Subject | synapses |
| Subject | synapse adhesion molecules |
| Subject | neurexins |
| Subject | autism |
| Genre | Text |
| Genre | Thesis |
Bibliographic information
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- This work is licensed under a Creative Commons Attribution Non Commercial 4.0 International license (CC BY-NC).
Preferred citation
- Preferred citation
- Choeb, R. and Südhof, T. (2023). A Representative Role for the Alternative Splicing of Synaptic Genes. Stanford Digital Repository. Available at https://purl.stanford.edu/bk221jr4480. https://doi.org/10.25740/bk221jr4480.
Collection
Undergraduate Theses, Department of Biology, 2022-2023
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- ryanch6@stanford.edu
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