Developmental Biology and Cancer Department, University College London Great Ormond Street Institute of Child Health, University College London, and National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, London WC1N 1EH, United Kingdom.
Wolfson Sensory, Pain and Regeneration Centre, King's College, London SE1 1UL, United Kingdom.
Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2322124121. doi: 10.1073/pnas.2322124121. Epub 2024 Nov 25.
Variants in the gene 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. 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 -knockout (-KO) mouse model by conditional activation of stabilized β-catenin in vascular endothelial cells. We hypothesized that in the cochlea microvasculature, β-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 KO mice stabilizing β-catenin in vascular endothelial cells alone rescued defects in cochlear vascular barrier function, restored dysregulated expression of endothelial cell disease biomarkers ( and ), and prevented progressive outer hair cell death and hearing loss. Single-cell transcriptome profiling of human cochleas showed expression by fibrocytes and glial cells while receptor gene expression ( and ) 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 β-catenin regulation of target gene expression within cochlear endothelial cells is sufficient to maintain a cochlear microenvironment critical for hair cell survival.
基因中的变异导致诺里病，这是一种严重的双重感觉障碍，其特征是视网膜血管发育中断导致先天性失明和进行性听力损失，伴有感觉毛细胞死亡。编码分泌信号分子诺林。诺林在耳蜗中的作用尚未完全了解。我们研究了在血管内皮细胞中稳定的β-连环蛋白条件激活是否可以改善 - 敲除（-KO）小鼠模型中的诺里病耳蜗病理学。我们假设在耳蜗微血管中，β-连环蛋白是诺林结合内皮细胞表面受体的主要下游细胞内效应物，并且恢复这种信号通路足以防止感觉毛细胞死亡和听力损失。我们表明，仅用他莫昔芬诱导 KO 小鼠稳定血管内皮细胞中的β-连环蛋白就可以挽救耳蜗血管屏障功能的缺陷，恢复内皮细胞疾病生物标志物（和）的失调表达，并防止外毛细胞进行性死亡和听力损失。人类耳蜗的单细胞转录组分析显示纤维细胞和成胶质细胞表达，而受体基因表达（和）与血管内皮细胞一致。我们的研究结果支持这样的结论，即血管内皮细胞是小鼠和人类耳蜗中诺林信号的主要靶标，并且恢复β-连环蛋白对耳蜗内皮细胞中靶基因表达的调节足以维持对毛细胞存活至关重要的耳蜗微环境。
