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Published on: July 10, 2018
Abnormal corneal epithelial maintenance in mice heterozygous for the micropinna microphthalmia mutation Mp
Panagiotis Douvaras1, Natalie J Dorà2, Richard L Mort1
1Genes and Development Group, Centre for Integrative Physiology, Clinical Sciences, University of Edinburgh Medical School, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
Abstract:
We investigated the corneal morphology of adult Mp/+ mice, which are heterozygous for the micropinna microphthalmia mutation, and identified several abnormalities, which implied that corneal epithelial maintenance was abnormal. The Mp/+ corneal epithelium was thin, loosely packed and contained goblet cells in older mice. Evidence also suggested that the barrier function was compromised. However, there was no major effect on corneal epithelial cell turnover and mosaic patterns of radial stripes indicated that radial cell movement was normal. Limbal blood vessels formed an abnormally wide limbal vasculature ring, K19-positive cells were distributed more widely than normal and K12 was weakly expressed in the peripheral cornea. This raises the possibilities that the limbal-corneal boundary was poorly defined or the limbus was wider than normal. BrdU label-retaining cell numbers and quantitative clonal analysis suggested that limbal epithelial stem cell numbers were not depleted and might be higher than normal. However, as corneal epithelial homeostasis was abnormal, it is possible that Mp/+ stem cell function was impaired. It has been shown recently that the Mp mutation involves a chromosome 18 inversion that disrupts the Fbn2 and Isoc1 genes and produces an abnormal, truncated fibrillin-2(MP) protein. This abnormal protein accumulates in the endoplasmic reticulum (ER) of cells that normally express Fbn2 and causes ER stress. It was also shown that Fbn2 is expressed in the corneal stroma but not the corneal epithelium, suggesting that the presence of truncated fibrillin-2(MP) protein in the corneal stroma disrupts corneal epithelial homeostasis in Mp/+ mice.
Insights
The micropinna (Mp/+) mouse model exhibits corneal abnormalities due to a fibrillin-2 mutation, impacting corneal epithelial maintenance and barrier function. Stem cell numbers appear normal, but their function may be impaired.
Area of Science:
- Ophthalmology
- Genetics
- Developmental Biology
Background:
- The micropinna (Mp/+) mouse model carries a heterozygous mutation affecting corneal morphology.
- Previous studies indicated abnormal corneal epithelial maintenance in these mice.
Purpose of the Study:
- To investigate the corneal morphology and epithelial homeostasis in adult Mp/+ mice.
- To elucidate the underlying mechanisms of corneal abnormalities associated with the Mp mutation.
Main Methods:
- Analysis of corneal epithelial morphology, cell packing, and goblet cell presence.
- Assessment of corneal epithelial barrier function and cell turnover.
- Evaluation of limbal vasculature, K19 and K12 expression, and limbal epithelial stem cell populations using BrdU labeling and clonal analysis.
Main Results:
- Mp/+ mice displayed thin, loosely packed corneal epithelium with goblet cells in older individuals, suggesting compromised barrier function.
- Radial cell movement and corneal epithelial cell turnover were largely unaffected.
- Abnormalities included a widened limbal vasculature, expanded K19-positive cell distribution, and reduced K12 expression in the peripheral cornea.
- Limbal epithelial stem cell numbers were not depleted and potentially increased, but stem cell function might be impaired.
- The Mp mutation disrupts Fbn2 and Isoc1 genes, leading to abnormal fibrillin-2(MP) protein accumulation in the endoplasmic reticulum, causing ER stress and disrupting corneal epithelial homeostasis via stromal effects.
Conclusions:
- The Mp/+ mouse cornea exhibits significant epithelial abnormalities and compromised barrier function.
- While limbal stem cell numbers are not reduced, their function appears impaired, contributing to abnormal corneal epithelial homeostasis.
- The fibrillin-2(MP) proteinopathy arising from the Mp mutation disrupts corneal homeostasis, likely through ER stress induced by stromal accumulation of the abnormal protein.
