Journal Club: Blood vessel barrier function change in both eyes and ears in Norris Disease

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Today's journal article

Patel A, Pauzuolyte V, Ingham NJ, Leong YC, Berger W, Steel KP, Sowden JC. Rescue of cochlear vascular pathology prevents sensory hair cell loss in Norrie disease. 

Why I picked this article

Another cochlear pathophysiology article in PNAS! 

This study investigates the pathophysiology in the cochlea (and the retina) using a transgenic animal model of Norris Disease. 

According to the Norris disease foundation (https://norriedisease.org.uk/about-norrie-disease/), Norris disease is a genetic disorder associated with vision loss at birth. A large proportion of those affected also have progressive hearing loss. It is a genetic disease caused by a variation in the NPD gene on the X chromosome, and is recessive. According to the foundation, there are around 40 cases known in the UK, and 500 globally. 

Past research suggests that the pathology of blindness in the retina comes from degeneration or abnormality of blood vessels. The pathology information in the cochlea causing hearing loss is less understood, due to the challenges associated with the inaccessibility of the ear; abnormality in the retina can be monitored in patients using diagnostic tools, while the same is not available for the cochlea. Pathologies in the cochlea can be speculated based on the post-mortem study (i.e. study of ear tissues donated after death for research), which shows a mixture of pathologies in different areas of the cochlea. 

This study uses an animal model where the NPD gene has been inactivated to understand what other proteins and cellular changes are associated with Norris disease. The study focus on the role of a protein called "β-catenin" and its role in the pathology. 

Some of the research findings

Animal model:

This study used a combination of genetic alterations to generate transgenic mice, where the Npd gene is not functional, and the protein β-catenin is stabilised. 

  • Mice lines used were: 
  • Ctnnb1flex3 mice - have a gene with a modification when activated with the Cre enzyme, which modifies the Ctnnb1 gene. 
  • Cdh5CreERT2 mice - have a genetic modification to produce "Cre" protein in cells of blood vessels (= endothelial cells) when stimulated by tamoxifen. 
  • Npd knockout mouse
  • The mixed mice that will be used in analyses are: 
    • Cdh5CreERT2; Ctnnbflex3/+;Ndp-KO - when stimulated with tamoxifen, genetic modification results in producing stabilised β-catenin in blood vessel cells. Npd gene is also inactivated. 
    • Cdh5CreERT2; Ctnnbflex3/+; WT pups - when stimulated with tamoxifen, genetic modification results in producing stabilised β-catenin in blood vessel cells. Npd gene is normal. 
    • For the above, tamoxifen was used at 10-day-old age. 
    • The group without tamoxifen is the control. 
  • Human gene expression from foetal cochlea (early development, during blood vessel development) was also analysed. "Human fetal cochlea samples provided by the Human Developmental Biology Resource with ethics approval were analyzed by 10× single-cell RNA sequencing and the Seurat package." Data available in "Array Express E-MTAB- 14063."

Findings: 

  • Norris disease model (Cdh5CreERT2; Ctnnbflex3/+;Ndp-KO without tamoxifen) developed vascular degeneration in the retina by 2-month old. In comparison, Norris disease + β-catenin stabilisation model (Cdh5CreERT2; Ctnnbflex3/+;Ndp-KO with tamoxifen) had less of such pathology. 
  • When mRNA levels were investigated as the measure of protein production in cells, genes such as Cldn5, Sox17 and Abcb1a were increased in the β-catenin stabilisation group. Noting that these genes and resultant proteins are important proteins in blood vessel cells. 
  • In the cochlea, the spiral ligament and stria vascularis (i.e. area in the cochlea full of small blood vessels, and are important for hearing) were investigated. Similar to the retina, loss of barrier function (as measured by the amount of Cldn5 protein) in the blood vessel was observed in the Norris disease model. This was mitigated by β-catenin stabilisation. 
Blood vessels in the cochlea of Norris disease model mice. Patel et al. (2025)

  • In the cochlea, Norris disease model (Cdh5CreERT2; Ctnnbflex3/+;Ndp-KO without tamoxifen) was associated with a significant loss of the auditory sensory cells (in particular, outer hair cells), which was mitigated in Norris disease + β-catenin stabilisation model (Cdh5CreERT2; Ctnnbflex3/+;Ndp-KO with tamoxifen). 
  • In foetal human cochlea analysis, at 15 post-conception weeks, NDP protein was found in what appear to be glia or fibrocytes of the cochlea. The authors reported associated proteins in the blood vessel cells. 

Haruna's takeaway

The blood vessel change as part of pathology is really the interesting part of this publication, and is shown nicely by using blood vessel visualisation, and also leakiness check using dyes in the animal model. This is also eye + ear paper! It is interesting to note how both the cochlea and the retina have a special barrier on the small blood vessels, just like the brain. While eyes are easier to examine in person, ear pathology is hard. But now with this publication and others, there are more example cases where the degeneration of blood vessels in the retina is "matched" by similar blood vessel pathology in the cochlea. Perhaps we should check hearing when the retinal blood vessels are damaged. 

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This is Haruna's 18/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.