Progressive Optic Neuropathy in Hydrocephalic Ccdc13 Mutant Mice Caused by Impaired Axoplasmic Transport at the Optic Nerve Head

作者：Mingjuan Wu, Xinyi Zhao, Shanzhen Peng, Xiaoyu Zhang, Jiali Ru, Lijing Xie, Tao Wen, Yingchun Su, Shujuan Xu, Dianlei Guo, Jianmin Hu, Haotian Lin, Tiansen Li, Chunqiao Liu · 发表于：Investigative Ophthalmology & Visual Science · 年份：2024 · DOI：10.1167/iovs.65.13.5 · 被引用次数：1 · 研究领域：Cerebrospinal fluid and hydrocephalus、Mitochondrial Function and Pathology、Head and Neck Surgical Oncology

Purpose: Optic nerve head (ONH) atrophy is frequently associated with hydrocephalic conditions. Cerebrospinal fluid (CSF)-containing meninges form a subarachnoid space that terminates at the ONH, which physically impacts it. This study aims to characterize optic neuropathy in congenital hydrocephalic mice with genetic disruption of the Ccdc13 gene. Methods: The ccdc13 germline knockout mice were generated. The hydrocephalus phenotype and subarachnoid space surrounding the optic nerve were evaluated using routine histology and Evans blue stain. Optic neuropathy was examined with immunohistochemistry and transmission electron microscopy (TEM). Axon transport was indicated by cholera toxin subunit B (CTB) fluorescence conjugate. Retinal function was evaluated by electroretinography (ERG), and Ccdc13 expression was revealed by a knock-in Gfp reporter. Results: Ccdc13 mutant mice manifested hydrocephalus at birth. ONH displacement, or negative cupping, and enlarged subarachnoid space at the optic terminus occurred as early as 1 month after birth. Intraocular pressure (IOP) was normal. Optic neuropathy was first observed at the ONH, followed by a distal-to-proximal progression of optic nerve pathology indicated by alteration of axonal ultrastructure and deposition of unphosphorylated neurofilament heavy chain. Anterograde axonal transport was also hampered. Retinal ganglion cell (RGC) function was compromised as early as postnatal day 21 (P21), along with reduced neurofilament heav...