Speaker
Description
SYNGAP1, encoding Ras/Rap GTPase-activating protein, is a critical gene involved in synaptic signaling and neurodevelopment. Mutations in SYNGAP1 are associated with intellectual disability and autism spectrum disorder (ASD). However, the specific functions of its multiple isoforms, generated by alternative splicing and transcription start sites, remain poorly understood. Current methods for studying SYNGAP1 functions rely on animal models, which do not fully recapitulate human neurodevelopment. This project aims to elucidate the roles of different SYNGAP1 isoforms using human cerebral organoids as an alternative to animal models. Cerebral organoids, derived from pluripotent stem cells, offer a promising 3R approach by mimicking the human brain architecture and functionality. We will employ cutting-edge techniques including single-cell RNA sequencing, CRISPR-based gene perturbation, and BaseScope in situ hybridization to comprehensively profile SYNGAP1 isoform expression, manipulate their levels, and visualize their spatiotemporal distribution across different developmental timepoints: 15, 30, 60 days, roughly equivalent to 4, 10, 18 post-conceptional weeks of human development in vivo. By developing this innovative 3D model system, we aim to uncover isoform-specific roles of SYNGAP1 in human brain development. Our approach will not only advance mechanistic understanding of SYNGAP1 biology, but also exemplify how cerebral organoids can serve as a powerful alternative to animal use.
| Author(s) | Ivanna Kupryianchyk-Schultz*1, Daniel Bauersachs2, Ralf Kühn2, Manuel Irimia 3, Sarah Shoichet4, Agnieszka Rybak-Wolf1 |
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| Affiliation(s) | "1. MDC, Organoid Platform 2. MDC, Transgenics Platform 3. MDC, BIMSB 4. Charité - Universitätsmedizin Berlin, Berlin, Germany" |
