Mapping and understanding gene expression in the nervous system with chemical and spatial lenses
The brain is a highly structured functional tissue, the study of which ranges multiple spatial scales and involves diverse techniques. In my talk, I will share two stories where new perspectives and tools to appreciate and probe the nervous system bring biological insights. The first part is about how a naturally occurring chemical modification on messenger RNAs, N6-methyladenosine (m6A), contributes to learning and memory through an m6A-selective RNA binding protein YTHDF1. We found that the mice depleted of YTHDF1 showed defects in hippocampus-dependent learning and memory and long-term potentiation (LTP). In the hippocampus, we showed that RNA transcripts bound by YTHDF1 enriched key proteins for synaptic transmission and LTP. Molecularly, YTHDF1 is critical for the protein translation boost following neuronal stimuli. This work presents one of the first in vivo examples showing the physiology relevance of the translational promotion effect of m6A. The second part is building a spatial cell atlas of the mouse brain via light microscopy-based spatial transcriptomics profiling and molecular barcoding. Spatial molecular profiling opens opportunities for understanding cell-type distribution, tissue organization principles, and cell-cell interactions. I will present a comprehensive spatial atlas of the adult mouse central nervous system (CNS), with over one million cells at subcellular and molecular resolution, clustering and distribution of molecularly defined cell types and tissue domains, and quantitative tropisms of the viral tools used in CNS gene delivery. My future research will further integrate chemical and spatial profiling approaches to understand tissue health and disease.