Rescue of cochlear vascular pathology prevents sensory hair cell loss in Norrie disease

• 成果类型: Article
• 署名作者: Patel, Aara; Pauzuolyte, Valda; Ingham, Neil J.; Leong, Yeh Chwan; Berger, Wolfgang; Steel, Karen P.; Sowden, Jane C.
• 署名单位: University of London; University College London; University of London; King's College London; University of Zurich; University of Zurich; Zurich Center Integrative Human Physiology (ZIHP); University of Zurich; University of Zurich; Swiss Federal Institutes of Technology Domain; ETH Zurich
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14839
• DOI: 10.1073/pnas.2322124121
• 发表日期: 2024-12-03
• 关键词: blood-brain-barrier; familial exudative vitreoretinopathy; inner-ear; adhesion molecule; p-glycoprotein; hearing-loss; candidate gene; c-kit; frizzled-4; mutations

摘要

Variants in the gene NDP cause Norrie disease, a severe dual- sensory disorder characterized by congenital blindness due to disrupted retinal vascular development and progressive hearing loss accompanied by sensory hair cell death. NDP encodes the secreted signaling molecule norrin. The role of norrin in the cochlea is incompletely understood. We investigated whether the Norrie disease cochlear pathology can be ameliorated in an Ndp- knockout (Ndp- KO) mouse model by conditional activation of stabilized f3- catenin in vascular endothelial cells. We hypothesized that in the cochlea microvasculature, f3- catenin is the primary downstream intracellular effector of norrin binding to endothelial cell surface receptors and that restoration of this signaling pathway is sufficient to prevent sensory hair cell death and hearing loss. We show that tamoxifen induction of Cdh5CreERT2;Ctnnb1flex3/+;Ndp- KO mice stabilizing f3- catenin in vascular endothelial cells alone rescued defects in cochlear vascular barrier function, restored dysregulated expression of endothelial cell disease biomarkers (Cldn5, Abcb1a, Slc7a1, and Slc7a5), and prevented progressive outer hair cell death and hearing loss. Single- cell transcriptome profiling of human cochleas showed NDP expression by fibrocytes and glial cells while receptor gene expression (FZD4, TSPAN12, LRP5, and LRP6) coincided in vascular endothelial cells. Our findings support the conclusion that vascular endothelial cells are a primary target of norrin signaling in the cochlea of mice and humans and restoration of f3- catenin regulation of target gene expression within cochlear endothelial cells is sufficient to maintain a cochlear microenvironment critical for hair cell survival.