RNA isoforms influence cell identity and function. However, a comprehensive brain isoform map was lacking. We analyze single-cell RNA isoforms across brain regions, cell subtypes, developmental time points and species. For 72% of genes, full-length isoform expression varies along one or more axes. Splicing, transcription start and polyadenylation sites vary strongly between cell types, influence protein architecture and associate with disease-linked variation. Additionally, neurotransmitter transport and synapse turnover genes harbor cell-type variability across anatomical regions. Regulation of cell-type-specific splicing is pronounced in the postnatal day 21-to-postnatal day 28 adolescent transition. Developmental isoform regulation is stronger than regional regulation for the same cell type. Cell-type-specific isoform regulation in mice is mostly maintained in the human hippocampus, allowing extrapolation to the human brain. Conversely, the human brain harbors additional cell-type specificity, suggesting gain-of-function isoforms. Together, this detailed single-cell atlas of full-length isoform regulation across development, anatomical regions and species reveals an unappreciated degree of isoform variability across multiple axes.

RNA 同工型影响细胞身份和功能。然而，缺乏全面的大脑亚型图。我们分析跨大脑区域、细胞亚型、发育时间点和物种的单细胞 RNA 亚型。对于 72% 的基因，全长异构体表达沿着一个或多个轴变化。不同细胞类型之间的剪接、转录起始点和聚腺苷酸化位点差异很大，影响蛋白质结构并与疾病相关变异相关。此外，神经递质运输和突触转换基因在不同的解剖区域中存在细胞类型的变异性。细胞类型特异性剪接的调节在出生后第 21 天到出生后第 28 天的青春期过渡中很明显。对于同一细胞类型，发育亚型调节比区域调节更强。小鼠中细胞类型特异性亚型调节主要维持在人类海马体中，因此可以外推到人类大脑。相反，人脑具有额外的细胞类型特异性，表明存在功能获得亚型。总之，这个详细的单细胞图谱显示了整个发育、解剖区域和物种的全长亚型调节，揭示了跨多个轴的亚型变异性未被认识到的程度。