1. SOX9-COL9A3-dependent regulation of choroid plexus epithelial polarity governs blood-cerebrospinal fluid barrier integrity.
- Author
-
Vong KI, Ma TC, Li B, Leung TCN, Nong W, Ngai SM, Hui JHL, Jiang L, and Kwan KM
- Subjects
- Animals, Basement Membrane metabolism, Collagen Type IX genetics, Electrolytes cerebrospinal fluid, Epithelial Cells metabolism, Epithelium metabolism, Extracellular Matrix metabolism, Gene Deletion, Gene Knockdown Techniques, Mice, Knockout, Microtubules metabolism, Tight Junctions metabolism, Transcription, Genetic, Mice, Blood metabolism, Cell Polarity, Cerebrospinal Fluid metabolism, Choroid Plexus metabolism, Collagen Type IX metabolism, Epithelial Cells cytology, SOX9 Transcription Factor metabolism
- Abstract
The choroid plexus (CP) is an extensively vascularized neuroepithelial tissue that projects into the brain ventricles. The restriction of transepithelial transport across the CP establishes the blood-cerebrospinal fluid (CSF) barrier that is fundamental to the homeostatic regulation of the central nervous system microenvironment. However, the molecular mechanisms that control this process remain elusive. Here we show that the genetic ablation of Sox9 in the hindbrain CP results in a hyperpermeable blood-CSF barrier that ultimately upsets the CSF electrolyte balance and alters CSF protein composition. Mechanistically, SOX9 is required for the transcriptional up-regulation of Col9a3 in the CP epithelium. The reduction of Col9a3 expression dramatically recapitulates the blood-CSF barrier defects of Sox9 mutants. Loss of collagen IX severely disrupts the structural integrity of the epithelial basement membrane in the CP, leading to progressive loss of extracellular matrix components. Consequently, this perturbs the polarized microtubule dynamics required for correct orientation of apicobasal polarity and thereby impedes tight junction assembly in the CP epithelium. Our findings reveal a pivotal cascade of SOX9-dependent molecular events that is critical for construction of the blood-CSF barrier., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
- Full Text
- View/download PDF