Disruption of Ccdc13, a cilia protein, causes congenital hydrocephalus and optic nerve dystrophy

Abstract

Purpose : Purpose: Optic nerve (ON) atrophy is frequently associated with hydrocephalic disease, plausibly resulting from aberrant production and circulation of the cerebrospinal fluid (CSF) through the periphery optic nerve sheath. However, the precise relationship between CSF production/circulation and optic nerve dystrophy remains uncovered. This study aims to investigate optic nerve and ganglion cell (RGC) pathogenesis in a hydrocephalus mouse model and compare it with that of acute hypertension and optic nerve crush injuries.

Methods : Ccdc13 was genetically disrupted to generate germline knockout mice. Hydrocephalus phenotype was confirmed by histology analysis. The flow path of CSF and the ON subarachnoid space were evaluated by Evans blue dye. RGC function was analyzed by pattern electroretinography (PERG). Acute ocular hypertension and optic nerve crush were used to model RGC and ON injuries. Immunostaining and/or transmission electron microscopy (TEM) were used to detect optic nerve damage.

Results : Results: Ccdc13 mutant mice manifested hydrocephalus at birth, with excess CSF production and abnormal ventricular cilia motion. Optic nerve subarachnoid space was enlarged with reduced optic nerve glia mantle astrocyte processes. Mutant mice showed significantly reduced PERG amplitudes and decreased retinal neural fiber density with discontinued axonal bulbs. Immunofluorescence showed that the optic nerve neurofilaments and microtubules of the Ccdc13^KO mice were fractured. Optic nerve dystrophy in Ccdc13^KO hydrocephalus mice is similar to that of acute ocular hypertension or optic nerve crush injury models, with fragmentation of neurofilaments and microtubules. Slow but progressive RGC loss was additionally observed in Ccdc13^KO mice. Finally, Ccdc13 is undetectable in retina neurons.

Conclusions : The optic nerve dystrophy of the Ccdc13 hydrocephalic mutants is likely due to the excess CSF fluid in the optic nerve subarachnoid space. The current study provided a useful genetically engineered mouse model for studying mechanisms of optic nerve atrophy related to congenital hydrocephalus.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.