RESUMEN
Retinal ganglion cells (RGCs) are the neurons in the retina which directly project to the brain and transmit visual information along the optic nerve. Glaucoma, one of the leading causes of blindness, is characterized by elevated intraocular pressure (IOP) and degeneration of the optic nerve, which is followed by RGC death. Currently, there are no clinical therapeutic drugs or molecular interventions that prevent RGC death outside of IOP reduction. In order to overcome these major barriers, an increased number of studies have utilized the following combined analytical methods: well-established rodent models of glaucoma including optic nerve injury models and transcriptomic gene expression profiling, resulting in the successful identification of molecules and signaling pathways relevant to RGC protection. In this review, we present a comprehensive overview of pathological features in a variety of animal models of glaucoma and top differentially expressed genes (DEGs) depending on disease progression, RGC subtypes, retinal regions or animal species. By comparing top DEGs among those different transcriptome profiles, we discuss whether commonly listed DEGs could be defined as potential novel therapeutic targets in glaucoma, which will facilitate development of future therapeutic neuroprotective strategies for treatments of human patients in glaucoma.
RESUMEN
Molecular insights into the selective vulnerability of retinal ganglion cells (RGCs) in optic neuropathies and after ocular trauma can lead to the development of novel therapeutic strategies aimed at preserving RGCs. However, little is known about what molecular contexts determine RGC susceptibility. In this study, we show the molecular mechanisms underlying the regional differential vulnerability of RGCs after optic nerve injury. We identified RGCs in the mouse peripheral ventrotemporal (VT) retina as the earliest population of RGCs susceptible to optic nerve injury. Mechanistically, the serotonin transporter (SERT) is upregulated on VT axons after injury. Utilizing SERT-deficient mice, loss of SERT attenuated VT RGC death and led to robust retinal axon regeneration. Integrin ß3, a factor mediating SERT-induced functions in other systems, is also upregulated in RGCs and axons after injury, and loss of integrin ß3 led to VT RGC protection and axon regeneration. Finally, RNA sequencing analyses revealed that loss of SERT significantly altered molecular signatures in the VT retina after optic nerve injury, including expression of the transmembrane protein, Gpnmb. GPNMB is rapidly downregulated in wild-type, but not SERT- or integrin ß3-deficient VT RGCs after injury, and maintaining expression of GPNMB in RGCs via AAV2 viruses even after injury promoted VT RGC survival and axon regeneration. Taken together, our findings demonstrate that the SERT-integrin ß3-GPNMB molecular axis mediates selective RGC vulnerability and axon regeneration after optic nerve injury.