Comprehensive landscape of the human cellular membrane proteins' transcriptome over neurodevelopmental stages of brain organoid models

Abstract

The brain is unique in evolutionary terms, allowing humans to perform complex tasks such as thinking and memory formation. Likewise, the difficulty observed for many years in studying this organ is equally notorious. Fortunately, a recent and powerful cellular tool, the cerebral organoids ("minibrains"), have boosted the way we investigate brain development and neuronal disorders, such as Autism. However, little is known regarding the gene expression profile and further post-transcriptional events, such as alternative splicing (AS), of brain organoids' development in several time points. Concurrently, a number of OMICs technologies, such as RNA sequencing (RNA-seq), have been increasingly applied in translational research to elucidate the transcriptomics of druggable genes (e.g., EGFR in gliomas). Cellular membrane proteins ("surfaceome") are of particular clinical interest given their more drug-accessible cellular region and participation in the regulation of numerous processes. As a result, knowing their gene expression profiles and AS isoforms during brain organoids' neurodevelopmental stages could be key to enhance the use of this tool in precision medicine. In this project, we aim to comprehensively investigate the surfaceome's transcriptomic landscape of normal human cerebral organoid models throughout their neurodevelopmental stages with both "bulk" and also single-cell RNA-seq. In the end, we seek to discover in brain organoids a set of surfaceome genes and splicing isoforms distinct of the brain development and potential novel biomarkers to be explored in clinics in a broader context, including neuronal disorders and cancer. (AU)