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Although best known for its role in Alzheimer's disease (AD), tau is expressed throughout brain development, although it remains unclear when and which cell types this expression occurs and how it affects disease states in both fetal and neonatal periods. We thus sought to map tau mRNA and protein expression in the developing human brain at the cellular level using a combination of existing single-cell RNA sequencing (sc-RNAseq) data, RNA in situ hybridization (RNAscope), and immunohistochemistry (IHC). Using sc-RNAseq, we found that tau mRNA expression begins in radial glia but increases dramatically as migrating neuronal precursors mature. Specifically, TBR1  + maturing neurons and SYN  + mature neurons showed significantly higher mRNA expression than GFAP  + / NES  + radial glia or TBR2  + intermediate progenitors. By RNAscope, we found low levels of tau mRNA in subventricular zone (SVZ) radial glia and deep white matter intermediate progenitors, with an increase in more superficially located maturing and mature neurons. By total-tau IHC, the germinal matrix and SVZ showed little protein expression, although both RNAscope and sc-RNAseq showed mRNA, and Western blotting revealed significantly less protein in those areas compared with more mature regions. Induced pluripotent stem cell (iPSC)-derived cortical organoids showed a similar tau expression pattern by sc-RNAseq and RNAscope. Our results indicate that tau increases with neuronal maturation in both the developing fetal brain and iPSC-derived organoids and forms a basis for future research on regulatory mechanisms triggering the onset of tau gene transcription and translation, which may represent potential therapeutic targets for neurodegenerative tauopathies and neurodevelopmental disorders.

Increased Tau Expression Correlates with Neuronal Maturation in the Developing Human Cerebral Cortex