Retinal ganglion cell survival after severe optic nerve injury is modulated by crosstalk between JAK/STAT signaling and innate immune responses in the zebrafish retina

Chen, Si; Lathrop, Kira L.; Kuwajima, Takaaki; Gross, Jeffrey M.

doi:10.1101/2021.04.08.439090

Cited by 4 publications

(2 citation statements)

References 75 publications

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“…This suggests that RGC survival signals are more active in zebrafish retina. Recently, many studies have been seeking to identify such zebrafish-specific survival mechanisms, with the aim to develop therapy that can prevent death of mammalian RGCs ( Chen et al, 2021 ). Interestingly, loss of zebrafish Strip1 causes an elevated apoptotic stress response profile in embryonic retinas having a degree of overlap with adult RGCs post-ONI.…”

Section: Discussionmentioning

confidence: 99%

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Strip1 regulates retinal ganglion cell survival by suppressing Jun-mediated apoptosis to promote retinal neural circuit formation

Ahmed

Kojima

Masai

2022

eLife

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In the vertebrate retina, an interplay between retinal ganglion cells (RGCs), amacrine (AC), and bipolar (BP) cells establishes a synaptic layer called the inner plexiform layer (IPL). This circuit conveys signals from photoreceptors to visual centers in the brain. However, the molecular mechanisms involved in its development remain poorly understood. Striatin-interacting protein 1 (Strip1) is a core component of the striatin-interacting phosphatases and kinases (STRIPAK) complex, and it has shown emerging roles in embryonic morphogenesis. Here, we uncover the importance of Strip1 in inner retina development. Using zebrafish, we show that loss of Strip1 causes defects in IPL formation. In strip1 mutants, RGCs undergo dramatic cell death shortly after birth. AC and BP cells subsequently invade the degenerating RGC layer, leading to a disorganized IPL. Mechanistically, zebrafish Strip1 interacts with its STRIPAK partner, Striatin 3 (Strn3), and both show overlapping functions in RGC survival. Furthermore, loss of Strip1 or Strn3 leads to activation of the proapoptotic marker, Jun, within RGCs, and Jun knockdown rescues RGC survival in strip1 mutants. In addition to its function in RGC maintenance, Strip1 is required for RGC dendritic patterning, which likely contributes to proper IPL formation. Taken together, we propose that a series of Strip1-mediated regulatory events coordinates inner retinal circuit formation by maintaining RGCs during development, which ensures proper positioning and neurite patterning of inner retinal neurons.

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Section: Discussionmentioning

confidence: 99%

“…This suggests that RGC survival signals are more active in zebrafish retina. Recently, many studies are seeking to identify such zebrafish-specific survival mechanisms, with the aim to develop therapy that can prevent death of mammalian RGCs (Chen et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Strip1 regulates retinal ganglion cell survival by suppressing Jun-mediated apoptosis to promote retinal neural circuit formation

Ahmed

Kojima

Masai

2022

eLife

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Citrus extraction provides neuroprotective effect in optic nerve crush injury mice through P53 signaling pathway

Yang,

Chen,

et al. 2024

Journal of Functional Foods

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mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

Leach

Gross

2021

Preprint

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The retinal pigment epithelium (RPE) plays numerous critical roles in maintaining vision and this is underscored by the prevalence of degenerative blinding diseases like age-related macular degeneration (AMD), in which visual impairment is caused by progressive loss of RPE cells. In contrast to mammals, zebrafish possess the ability to intrinsically regenerate a functional RPE layer after severe injury. The molecular underpinnings of this regenerative process remain largely unknown yet hold tremendous potential for developing treatment strategies to stimulate endogenous regeneration in the human eye. In this study, we demonstrate that the mTOR pathway is activated in RPE cells post-genetic ablation. Pharmacological and genetic inhibition of mTOR activity impaired RPE regeneration, while mTOR activation enhanced RPE recovery post-injury, demonstrating that mTOR activity is necessary and sufficient for RPE regeneration in zebrafish. RNA-seq of RPE isolated from mTOR-inhibited larvae identified a number of genes and pathways dependent on mTOR activity at early and late stages of regeneration; amongst these were components of the immune system, which is emerging as a key regulator of regenerative responses across various tissue and model systems. Our results identify crosstalk between macrophages/microglia and the RPE, wherein mTOR activity in the RPE is required for recruitment of macrophages/microglia to the injury site. In turn, these macrophages/microglia reinforce mTOR activity in regenerating RPE cells. Interestingly, the function of macrophages/microglia in maintaining mTOR activity in the RPE appeared to be inflammation-independent. Taken together, these data identify mTOR activity as a key regulator of RPE regeneration and link the mTOR pathway to immune responses in facilitating RPE regeneration.

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Retinal ganglion cell survival after severe optic nerve injury is modulated by crosstalk between JAK/STAT signaling and innate immune responses in the zebrafish retina

Cited by 4 publications

References 75 publications

Strip1 regulates retinal ganglion cell survival by suppressing Jun-mediated apoptosis to promote retinal neural circuit formation

Strip1 regulates retinal ganglion cell survival by suppressing Jun-mediated apoptosis to promote retinal neural circuit formation

Citrus extraction provides neuroprotective effect in optic nerve crush injury mice through P53 signaling pathway

mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

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