An integrated multi-omic atlas of the choroid plexus highlights conserved molecular programs of epithelial function

Abstract

The choroid plexus (ChP) is a specialized epithelial tissue responsible for production of cerebrospinal fluid (CSF), maintenance of the blood-CSF barrier and regulation of CSF-borne signaling factors. However, despite the ChP's central role in CSF homeostasis, conserved molecular programs of ChP epithelial function across species and conditions remain incompletely defined. In this study, we integrated eight mouse and human single-cell/nucleus RNA-seq datasets to build a multi-species ChP atlas capturing major epithelial, stromal, vascular, and immune populations. Cross-dataset differential expression identified a conserved epithelial gene program encompassing ion transport, barrier function, ciliogenesis, and secretory signaling, while prioritizing understudied genes including CLIC6 and VAT1L. Co-expression network analysis resolved conserved epithelial meta-programs, and transcription factor regulatory inference identified OTX2, MSX1, and GLIS3 among conserved regulators of epithelial gene expression. We also generated a novel Visium HD spatial transcriptomic atlas of mouse fourth-ventricle ChP to orthogonally validate epithelial modules. Lastly, cross-tissue analyses revealed substantial transcriptional overlap between ChP and retinal pigment epithelium, including shared epithelial genes and OTX2-associated regulatory relationships. Together, these findings define conserved molecular programs of ChP epithelial specialization, nominate candidate regulators for functional investigation, and provide an integrated cross-species and spatial resource for studying ChP physiology.