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

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...

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Autores principales:	Rody Kingston, Dwarkesh Amin, Sneha Misra, Jeffrey M. Gross, Takaaki Kuwajima
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/6c6ef29e02cd4ae3b75cb99529550d17
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spelling	oai:doaj.org-article:6c6ef29e02cd4ae3b75cb99529550d172021-11-25T05:51:20ZSerotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury1553-73901553-7404https://doaj.org/article/6c6ef29e02cd4ae3b75cb99529550d172021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594818/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Molecular 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. Author summary Retinal ganglion cells (RGCs) are the only neurons in the retina that convey visual information to the brain, doing so via the optic nerve. Major causes of optic nerve damage and subsequent RGC death are ocular trauma and optic neuropathies. At the end-stage pathology in the retina, remaining RGCs have high neuroprotective capacity, and active resilience mechanisms exist. In contrast, in this study, we demonstrate neurodegenerative mechanisms based on the early susceptibility of peripheral ventrotemporal (VT) RGCs to degeneration after optic nerve injury. We identified the serotonin transporter (SERT) as the factor mediating VT RGC vulnerability and axon regeneration. Loss of SERT affected activation of integrin β3 and gene expression in the peripheral VT retina, leading to peripheral VT RGC protection and axon regeneration. Interestingly, GPNMB, a newly identified molecule mediating neuroprotection and axon regeneration in this study, is expressed in all retinal regions. However, GPNMB expression is acutely downregulated by the presence of SERT in the peripheral VT retina, leading to regional differential vulnerability of RGCs. These findings provide new molecular mechanisms underlying selective RGC vulnerability and clues that could inform further neuroprotective and regenerative strategies.Rody KingstonDwarkesh AminSneha MisraJeffrey M. GrossTakaaki KuwajimaPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Rody Kingston Dwarkesh Amin Sneha Misra Jeffrey M. Gross Takaaki Kuwajima Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury
description	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. Author summary Retinal ganglion cells (RGCs) are the only neurons in the retina that convey visual information to the brain, doing so via the optic nerve. Major causes of optic nerve damage and subsequent RGC death are ocular trauma and optic neuropathies. At the end-stage pathology in the retina, remaining RGCs have high neuroprotective capacity, and active resilience mechanisms exist. In contrast, in this study, we demonstrate neurodegenerative mechanisms based on the early susceptibility of peripheral ventrotemporal (VT) RGCs to degeneration after optic nerve injury. We identified the serotonin transporter (SERT) as the factor mediating VT RGC vulnerability and axon regeneration. Loss of SERT affected activation of integrin β3 and gene expression in the peripheral VT retina, leading to peripheral VT RGC protection and axon regeneration. Interestingly, GPNMB, a newly identified molecule mediating neuroprotection and axon regeneration in this study, is expressed in all retinal regions. However, GPNMB expression is acutely downregulated by the presence of SERT in the peripheral VT retina, leading to regional differential vulnerability of RGCs. These findings provide new molecular mechanisms underlying selective RGC vulnerability and clues that could inform further neuroprotective and regenerative strategies.
format	article
author	Rody Kingston Dwarkesh Amin Sneha Misra Jeffrey M. Gross Takaaki Kuwajima
author_facet	Rody Kingston Dwarkesh Amin Sneha Misra Jeffrey M. Gross Takaaki Kuwajima
author_sort	Rody Kingston
title	Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury
title_short	Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury
title_full	Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury
title_fullStr	Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury
title_full_unstemmed	Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury
title_sort	serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/6c6ef29e02cd4ae3b75cb99529550d17
work_keys_str_mv	AT rodykingston serotonintransportermediatedmolecularaxisregulatesregionalretinalganglioncellvulnerabilityandaxonregenerationafternerveinjury AT dwarkeshamin serotonintransportermediatedmolecularaxisregulatesregionalretinalganglioncellvulnerabilityandaxonregenerationafternerveinjury AT snehamisra serotonintransportermediatedmolecularaxisregulatesregionalretinalganglioncellvulnerabilityandaxonregenerationafternerveinjury AT jeffreymgross serotonintransportermediatedmolecularaxisregulatesregionalretinalganglioncellvulnerabilityandaxonregenerationafternerveinjury AT takaakikuwajima serotonintransportermediatedmolecularaxisregulatesregionalretinalganglioncellvulnerabilityandaxonregenerationafternerveinjury
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Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury

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