Liang Chen, Kerr Alicia, Qiu Yangfengzhong, Cristofoli Francesca, Van Esch Hilde, Fox Michael A, Mukherjee Konark
Developmental and Translational Neurobiology Center, Virginia Tech Carilion Research Institute, Roanoke, Virginia, United States.
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States.
Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5485-5496. doi: 10.1167/iovs.17-22399.
Optic nerve hypoplasia (ONH) is the most common cause of childhood congenital blindness in developed nations, yet the fundamental pathobiology of ONH remains unknown. The objective of this study was to employ a 'face validated' murine model to determine the timing of onset and the pathologic characteristics of ONH.
Based on the robust linkage between X-linked CASK haploinsufficiency and clinically diagnosed ONH, we hypothesized that heterozygous deletion of CASK (CASK(+/-)) in rodents will produce an optic nerve pathology closely recapitulating ONH. We quantitatively analyzed the entire subcortical visual system in female CASK(+/-) mice using immunohistochemistry, anterograde axonal tracing, toluidine blue staining, transmission electron microscopy, and serial block-face scanning electron microscopy.
CASK haploinsuffiency in mice phenocopies human ONH with complete penetrance, thus satisfying the 'face validity'. We demonstrate that the optic nerve in CASK(+/-) mice is not only thin, but is comprised of atrophic retinal axons and displays reactive astrogliosis. Myelination of the optic nerve axons remains unchanged. Moreover, we demonstrate a significant decrease in retinal ganglion cell (RGC) numbers and perturbation in retinothalamic connectivity. Finally, we used this mouse model to define the onset and progression of ONH pathology, demonstrating for the first time that optic nerve defects arise at neonatally in CASK(+/-)mice.
Optic nerve hypoplasia is a complex neuropathology of the subcortical visual system involving RGC loss, axonopathy, and synaptopathy and originates at a developmental stage in mice that corresponds to the late third trimester development in humans.
在发达国家，视神经发育不全（ONH）是儿童先天性失明的最常见原因，但ONH的基本病理生物学机制仍不清楚。本研究的目的是采用一种“表面验证”的小鼠模型来确定ONH的发病时间和病理特征。
基于X连锁的CASK单倍体不足与临床诊断的ONH之间的紧密联系，我们假设啮齿动物中CASK的杂合缺失（CASK(+/-)）将产生一种与ONH非常相似的视神经病理。我们使用免疫组织化学、顺行轴突追踪、甲苯胺蓝染色、透射电子显微镜和连续块面扫描电子显微镜对雌性CASK(+/-)小鼠的整个皮质下视觉系统进行了定量分析。
小鼠中的CASK单倍体不足完全模拟了人类ONH，从而满足了“表面有效性”。我们证明，CASK(+/-)小鼠的视神经不仅细，而且由萎缩的视网膜轴突组成，并显示出反应性星形胶质细胞增生。视神经轴突的髓鞘形成保持不变。此外，我们证明视网膜神经节细胞（RGC）数量显著减少，视网膜丘脑连接受到干扰。最后，我们使用这个小鼠模型来定义ONH病理的发生和进展，首次证明CASK(+/-)小鼠在出生时就出现视神经缺陷。
视神经发育不全是皮质下视觉系统的一种复杂神经病理学，涉及RGC丢失、轴突病变和突触病变，起源于小鼠的一个发育阶段，该阶段相当于人类妊娠晚期的发育阶段。
