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NF-Protocadherin Regulates Retinal Ganglion Cell Axon Behaviour in the Developing Visual System.

ABSTRACT: Cell adhesion molecules play a central role in mediating axonal tract development within the nascent nervous system. NF-protocadherin (NFPC), a member of the non-clustered protocadherin family, has been shown to regulate retinal ganglion cell (RGC) axon and dendrite initiation, as well as influencing axonal navigation within the mid-optic tract. However, whether NFPC mediates RGC axonal behaviour at other positions within the optic pathway remains unclear. Here we report that NFPC plays an important role in RGC axonogenesis, but not in intraretinal guidance. Moreover, axons with reduced NFPC levels exhibit insensitivity to Netrin-1, an attractive guidance cue expressed at the optic nerve head. Netrin-1 induces rapid turnover of NFPC localized to RGC growth cones, suggesting that the regulation of NFPC protein levels may underlie Netrin-1-mediated entry of RGC axons into the optic nerve head. At the tectum, we further reveal a function for NFPC in controlling RGC axonal entry into the final target area. Collectively, our results expand our understanding of the role of NFPC in RGC guidance and illustrate that this adhesion molecule contributes to axon behaviour at multiple points in the optic pathway.

SUBMITTER: Leung LC

PROVIDER: S-EPMC4619323 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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NF-Protocadherin Regulates Retinal Ganglion Cell Axon Behaviour in the Developing Visual System.

Leung Louis C LC Harris William A WA Holt Christine E CE Piper Michael M

PloS one 20151021 10

Cell adhesion molecules play a central role in mediating axonal tract development within the nascent nervous system. NF-protocadherin (NFPC), a member of the non-clustered protocadherin family, has been shown to regulate retinal ganglion cell (RGC) axon and dendrite initiation, as well as influencing axonal navigation within the mid-optic tract. However, whether NFPC mediates RGC axonal behaviour at other positions within the optic pathway remains unclear. Here we report that NFPC plays an impor ...[more]

PMID: 26489017

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Project 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.

Dataset Information

NF-Protocadherin Regulates Retinal Ganglion Cell Axon Behaviour in the Developing Visual System.

Publications

NF-Protocadherin Regulates Retinal Ganglion Cell Axon Behaviour in the Developing Visual System.

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