Cell type-specific alternative splicing of cytoskeletal domains governs cell fate in the developing cerebral cortex

Alternative splicing regulates over 90% of multiexon mammlian genes, but its role in specifying neural progenitor cell (NPC) fates has not been explored. Our analyses of purified mouse NPCs and neurons from developing cerebral cortices revealed hundreds of conserved and differentially spliced exons that add or remove key protein domains, especially in genes regulating the cytoskeleton. TBR2-EGFP BAC transgenic mice, generated by GENSAT and outcrossed to FVB strain for 2 generations, drives EGFP expression in the vast majority of intermediate progenitors and neurons at E14.5. We FACS sorted EGFP positive (differentiating and differentiated neurons) and negative (neural progenitors) cells from the dorsal cerebral cortices of E14.5 TBR2-EGFP. Two replicates for each population were subjected to RNA sequencing. Alternatively spliced exons between the two populations (NPCs and neurons) were identified using MISO.