SOX9-COL9A3–dependent regulation of choroid plexus epithelial polarity governs blood–cerebrospinal fluid barrier integrity (2021) Keng Ioi Vong et al

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Significance
Tight regulation of the brain microenvironment is fundamental to proper neurologic function. The restriction of molecule entry into the central nervous system from the brain vascular endothelium has been well studied; however, far less is known about the molecular events that control permeability across the choroid plexus (CP) epithelium at the interface between the systemic circulation and cerebrospinal fluid (CSF). Our study establishes an essential role for SOX9 in the regulation of CP permeability. SOX9 induces the transcription of Col9a3, which mediates the microtubule dynamics necessary for orienting cell polarity and thereby assembling epithelial tight junctions. Our findings lay the groundwork for the manipulation of blood–CSF barrier permeability and expand our understanding of epithelial tissue integrity.

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.

PNAS.org: https://www.pnas.org/content/118/6/e2009568118

 

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MedicalXpress: Study brings new direction for treating neurological diseases

<< A research team from the School of Life Sciences at The Chinese University of Hong Kong (CUHK) has recently discovered that SOX9 protein is an essential regulatory factor of choroid plexus function that ensures the correct composition of cerebrospinal fluid (CSF). The finding, recently published in the prestigious scientific journal Proceedings of the National Academy of Sciences (PNAS), has provided the scientific community a novel understanding to the molecular regulatory mechanisms behind the function of the blood-CSF barrier and lays the groundwork for developing novel therapeutic strategies for preventing and treating neurodevelopmental disorders. >>

<< Some studies have confirmed that multiple neurodevelopmental disorders such as autism and Alzheimer's disease are associated with the functional impairment of the choroid plexus. One of the major causes underlying congenital hydrocephalus, an abnormal buildup of CSF in the brain ventricles that affects 1 out of every 1,000 newborns, is the abnormality of the choroid plexus. Moreover, it is recently found that, rather than neurons or glia in the central nervous system, it is SARS-CoV-2 infecting the choroid plexus that causes damaging of the epithelial blood-CSF barrier and leads to neurological complications in COVID-19 patients. Despite the pivotal role of the choroid plexus in brain homeostasis and development, how blood-CSF barrier function is regulated at the choroid plexus remains largely unknown. >>