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CASK 在视神经发育不全中的非细胞自主作用。

Non-Cell Autonomous Roles for CASK in Optic Nerve Hypoplasia.

机构信息

Center for Neurobiology Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia, United States.

Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, Virginia, United States.

出版信息

Invest Ophthalmol Vis Sci. 2019 Aug 1;60(10):3584-3594. doi: 10.1167/iovs.19-27197.

DOI:10.1167/iovs.19-27197
PMID:31425583
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6701874/
Abstract

PURPOSE

Heterozygous mutations in the essential X-linked gene CASK associate with optic nerve hypoplasia (ONH) and other retinal disorders in girls. CASK+/- heterozygous knockout mice with mosaic CASK expression exhibit ONH with a loss of retinal ganglion cells (RGCs) but no changes in retinal morphology. It remains unclear if CASK deficiency selectively affects RGCs or also affects other retinal cells. Furthermore, it is not known if CASK expression in RGCs is critical for optic nerve (ON) development and maintenance.

METHODS

The visual behavior of CASK+/- mice was assessed and electroretinography (ERG) was performed. Using a mouse line with a floxed CASK gene that expresses approximately 40% CASK globally in all cells (hypomorph) under hemizygous and homozygous conditions, we investigated effects of CASK reduction on the retina and ON. CASK then was completely deleted from RGCs to examine its cell-autonomous role. Finally, for the first time to our knowledge, we describe a hemizygous CASK missense mutation in a boy with ONH.

RESULTS

CASK+/- heterozygous mutant mice display reduced visual contrast sensitivity, but ERG is indistinguishable from wildtype. CASK hypomorph mice exhibit ONH, but deletion of CASK from RGCs in this background does not exacerbate the condition. The boy with ONH harbors a missense mutation (p.Pro673Leu) that destabilizes CASK and weakens the crucial CASK-neurexin interaction.

CONCLUSIONS

Our results demonstrate that mosaic or global reduction in CASK expression and/or function disproportionately affects RGCs. CASK expression in RGCs does not appear critical for cell survival, indicating a noncell autonomous role for CASK in the development of ON.

摘要

目的

X 连锁必需基因 CASK 的杂合突变与视神经发育不全（ONH）和女孩的其他视网膜疾病有关。具有马赛克 CASK 表达的 CASK+/-杂合敲除小鼠表现出 ONH，伴有视网膜神经节细胞（RGC）丧失，但视网膜形态无变化。目前尚不清楚 CASK 缺乏是否选择性地影响 RGC，还是也影响其他视网膜细胞。此外，尚不清楚 CASK 在 RGC 中的表达是否对视神经（ON）的发育和维持至关重要。

方法

评估 CASK+/- 小鼠的视觉行为并进行视网膜电图（ERG）检查。使用在所有细胞中（低聚物）以约 40%的 CASK 表达的 CASK 基因的 floxed 小鼠系，在半合子和纯合子条件下表达，我们研究了 CASK 减少对视网膜和 ON 的影响。然后，我们从 RGC 中完全删除 CASK，以检查其细胞自主性作用。最后，据我们所知，我们首次描述了一名患有 ONH 的男孩的杂合 CASK 错义突变。

结果

CASK+/-杂合突变小鼠显示出视觉对比敏感度降低，但 ERG 与野生型无法区分。CASK 低聚物小鼠表现出 ONH，但在这种背景下从 RGC 中删除 CASK 并没有加剧这种情况。患有 ONH 的男孩携带一个错义突变（p.Pro673Leu），该突变使 CASK 不稳定并削弱了关键的 CASK-神经连接素相互作用。

结论

我们的结果表明，CASK 表达和/或功能的镶嵌或整体减少不成比例地影响 RGC。RGC 中 CASK 的表达似乎对细胞存活不重要，表明 CASK 在 ON 发育中的非细胞自主作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/9fcc4ad3835e/i1552-5783-60-10-3584-f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/46b38a603652/i1552-5783-60-10-3584-f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/adcab78cf240/i1552-5783-60-10-3584-f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/7424626200a7/i1552-5783-60-10-3584-f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/96a49e908bc3/i1552-5783-60-10-3584-f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/9318ef80993b/i1552-5783-60-10-3584-f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/9fcc4ad3835e/i1552-5783-60-10-3584-f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/46b38a603652/i1552-5783-60-10-3584-f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/adcab78cf240/i1552-5783-60-10-3584-f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/7424626200a7/i1552-5783-60-10-3584-f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/96a49e908bc3/i1552-5783-60-10-3584-f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/9318ef80993b/i1552-5783-60-10-3584-f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c7/6701874/9fcc4ad3835e/i1552-5783-60-10-3584-f06.jpg

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