Regional Gene Expression in the Retina, Optic Nerve Head, and Optic Nerve of Mice with Optic Nerve Crush and Experimental Glaucoma

Abstract

A major risk factor for glaucomatous optic neuropathy is the level of intraocular pressure (IOP), which can lead to retinal ganglion cell axon injury and cell death. The optic nerve has a rostral unmyelinated portion at the optic nerve head followed by a caudal myelinated region. The unmyelinated region is differentially susceptible to IOP-induced damage in rodent models and human glaucoma. While several studies have analyzed gene expression changes in the mouse optic nerve following optic nerve injury, few were designed to consider the regional gene expression differences that exist between these distinct areas. We performed bulk RNA-sequencing on the retina and separately micro-dissected unmyelinated and myelinated optic nerve regions from naïve C57BL/6 mice, mice after optic nerve crush, and mice with microbead-induced experimental glaucoma (total = 36). Gene expression patterns in the naïve unmyelinated optic nerve showed significant enrichment of the Wnt, Hippo, PI3K-Akt, and transforming growth factor β pathways, as well as extracellular matrix–receptor and cell membrane signaling pathways, compared to the myelinated optic nerve and retina. Gene expression changes induced by both injuries were more extensive in the myelinated optic nerve than the unmyelinated region, and greater after nerve crush than glaucoma. Changes present three and fourteen days after injury largely subsided by six weeks. Gene markers of reactive astrocytes did not consistently differ between injury states. Overall, the transcriptomic phenotype of the mouse unmyelinated optic nerve was significantly different from immediately adjacent tissues, likely dominated by expression in astrocytes, whose junctional complexes are inherently important in responding to IOP elevation.

Comparison of the Biomechanics of the Mouse Astrocytic Lamina Cribrosa Between Glaucoma and Optic Nerve Crush Models

“… 13 In contrast, morphologic analysis of the LC of early glaucoma monkey eyes reported both thinning and thickening of the connective tissue beams, where areas with thinner beams had greater pore diameters, and areas with thicker beams had smaller pore diameters. 64 We are presently comparing the differential gene expression between healthy, crush injury, and glaucoma mouse models 65 to help explain the differences in the ex vivo biomechanical strain behavior found in this study and the differences in the microanatomy found elsewhere.…”

Environmentally friendly strategy for discovering the toxicity and mechanisms of nerve injury induced by acrylamide via network toxicology combined with molecular dynamics simulation

“…Studies have shown that nerve growth factor (NGF) promotes the formation of lamentous pseudopods and branches of axons through the PI3K-Akt signaling pathway [39] . The PI3K-Akt signaling pathway has been shown to be associated with ND [40][41][42] . Considering the regulatory effect of the PI3K-Akt signaling pathway and key targets such as TP53, PI3KCA, PIK3R1, RTK2, and GRB2 on nerve injury and combined with the ndings of previous studies, acrylamide was found to regulate the PI3K-Akt signaling pathway [43][44] .…”

The Hippo signalling pathway and its impact on eye diseases

“…Elevated IOP in rodent models produces optic neuropathology that was first observed in the unmyelinated portion of the optic nerve head, an area that corresponds to the lesion in human glaucoma 93 . Gene expression patterns in the unmyelinated optic nerve showed significant enrichment in the Hippo pathway compared to that in the myelinated optic nerve and retina 94 . The role of the Hippo signalling pathway in glaucoma is mainly reflected in the regulation of cell fibrosis and optic nerve protection.…”

“…93 Gene expression patterns in the unmyelinated optic nerve showed significant enrichment in the Hippo pathway compared to that in the myelinated optic nerve and retina. 94 The role of the Hippo signalling pathway in glaucoma is mainly reflected in the regulation of cell fibrosis and optic nerve protection.…”