Abnormal corneal epithelial maintenance in mice heterozygous for the micropinna microphthalmia mutation Mp.
Abnormal corneal epithelial maintenance in mice heterozygous for the micropinna microphthalmia mutation Mp.
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DOI：
10.1016/j.exer.2016.05.021
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发表时间：
2016-08
影响因子：
3.4
通讯作者：
West JD
中科院分区：
文献类型：
--
作者：
Douvaras P;Dorà NJ;Mort RL;Lodge EJ;Hill RE;West JD
我们研究了成年Mp/+小鼠的角膜形态，这是杂合子的小耳廓小眼突变，并确定了几个异常，这意味着角膜上皮的维护是异常的。在老年小鼠中，Mp/+角膜上皮较薄，松散，含有杯状细胞。证据还表明屏障功能受到损害。然而，对角膜上皮细胞更新没有重大影响，放射状条纹的镶嵌图案表明放射状细胞运动正常。角膜缘血管形成异常宽的角膜缘血管环，K19阳性细胞分布较正常角膜广泛，K12在周边角膜弱表达。这增加了边缘-角膜边界不清晰或利姆布斯比正常宽的可能性。BrdU标记保留细胞数量和定量克隆分析表明，角膜缘上皮干细胞数量没有耗尽，可能高于正常。然而，由于角膜上皮稳态异常，可能是Mp/+干细胞功能受损。最近已经表明，Mp突变涉及染色体18倒位，其破坏Fbn 2和Isoc 1基因，并产生异常的截短型β蛋白-2MP蛋白。这种异常蛋白质在正常表达Fbn 2的细胞的内质网（ER）中积累，并引起ER应激。还显示Fbn 2在角膜基质中表达，但在角膜上皮中不表达，表明角膜基质中截短的β蛋白-2MP蛋白的存在破坏了Mp/+小鼠中的角膜上皮稳态。杂合突变型Mp/+小鼠具有小的、异常的眼睛。角膜上皮较薄，排列疏松，有杯状细胞。角膜上皮细胞更新和放射状细胞运动正常。角膜-角膜缘边界模糊，利姆布斯较正常宽。间接测试表明，干细胞并没有耗尽，数量可能会增加。
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-2MP 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-2MP protein in the corneal stroma disrupts corneal epithelial homeostasis in Mp/+ mice. Heterozygous mutant Mp/+ mice have small, abnormal eyes. The corneal epithelium is thin, loosely packed and has goblet cells. Corneal epithelial cell turnover and radial cell movement appear normal. The cornea-limbal border is poorly defined and the limbus appears wider than normal. Indirect tests suggest stem cells are not depleted and numbers might be increased.