Abstract
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 β3, a factor mediating SERT-induced functions in other systems, is also upregulated in RGCs and axons after injury, and loss of integrin β3 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 β3-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 β3-GPNMB molecular axis mediates selective RGC vulnerability and axon regeneration after optic nerve injury.
Highlights
Mature retinal ganglion cell (RGC) axons that comprise the optic nerve degenerate, retinal ganglion cells (RGCs) die and blindness ensues after ocular trauma or during optic neuropathies such as glaucoma
To understand the molecular mechanisms underlying this susceptibility, we focused on serotonin transporter (SERT), which is upregulated on VT axons after optic nerve crush (ONC), and demonstrate that it functions in peripheral VT RGC death and impaired axon regeneration
We found that 95.0% of DN RGCs, 81.0% of DT RGCs and 77.2% of VN RGCs survived, while only 56.6% of VT RGCs survived (Fig 1B and 1C)
Summary
Mature retinal ganglion cell (RGC) axons that comprise the optic nerve degenerate, RGCs die and blindness ensues after ocular trauma or during optic neuropathies such as glaucoma. Ocular trauma, such as facial fractures, leads to 67% of patients who have ocular injuries, of which 4% present with optic nerve abnormalities [1]. RGC axons degenerate, and RGCs eventually die rapidly or chronically depending on the causes and magnitude of the damage [2]. There are no treatments or FDA-approved drugs that maintain the optic nerve and RGCs or that promote axon regeneration after ocular trauma or during optic neuropathies
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