Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury

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.

Subtype-specific survival and regeneration of retinal ganglion cells in response to injury

“…Peripheral VT RGCs were recently identified as the earliest population of RGCs susceptible to ONC injury. As such, they were found to be more vulnerable to degeneration after ONC compared to RGCs residing in other retinal regions (Kingston et al, 2021). In mice, nearly all RGCs in the VT region project to the ipsilateral side of the brain, while RGCs occupying other regions of the retina project to the contralateral side of the brain.…”

“…Additionally, some of the molecular mechanisms underlying the selective vulnerability of VT RGCs were recently identified. For example, serotonin transporter (SERT), which regulates refinement of ipsilateral projections and eye-specific segregation in brain targets during postnatal Frontiers in Cell and Developmental Biology frontiersin.org stages, was shown to contribute to higher VT RGC death after ONC (Kingston et al, 2021): SERT expression was significantly upregulated in injured VT axons and loss of SERT induced neuroprotection and axon regeneration of VT RGCs. This SERT-mediated death of injured VT RGCs occurs through activation of integrin β3, which binds to SERT and regulates many of its functions in the nervous system.…”

Integrated analyses reveal evolutionarily conserved and specific injury response genes in dorsal root ganglion

“…We noticed rat-preference DEGs with dramatic changes upon injury included genes that have been reported and validated in rat PNI models, including Hamp 50 , Serpina3n 51 , Tgm1 52 , Csrp3 53 , Reg3b 54 , Vip 52 , Tslp 55 and Atp2b4 (PMCA4) 56 . Thirty-four mouse-preference response DEGs were further screened, including documented genes in mouse nerve injury models, Slc6a4 /SERT1 57 , Inhbb 27 , Fgf3 58 , 59 , Plppr4 /PRG-1 60 , Gpr151 , and Anxa10 (Fig. 3f ).…”

Aldose reductase inhibition decelerates optic nerve degeneration by alleviating retinal microglia activation

“…Various approaches are being investigated to promote RGC survival and RGC regeneration, including gene 5 , 12 – 15 and stem cell replacement therapies 16 – 19 . Using the optic nerve crush (ONC) model, we induce acute axonal trauma to investigate the underlying mechanisms of RGC survival and axon regeneration 5 , 20 .…”