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Thesis (Dec 11, 2025) Mechanisms regulating retinal ganglion cell development and function

Brown TW

DOI: >>

Featured image for “Mechanisms regulating retinal ganglion cell development and function”

In his thesis, Brown investigates the molecular and cellular mechanisms regulating retinal ganglion cell (RGC) development and function. Visual function was assessed using the OptoDrum system, which quantified contrast perception and spatial frequency thresholds via the optomotor response in 8–14-week-old mice under photopic conditions. The thesis demonstrates that the transcription factor POU3F1 is required for the formation of contralaterally projecting RGCs. In addition, it shows that glial cell exocytosis is crucial for proper axonal targeting to circadian centers of the brain and for the development of circadian photoentrainment. Together, these findings describe two distinct stages of RGC development and the classes of RGCs generated, focusing on transcriptional regulation and glial-dependent mechanisms underlying retinal circuit formation.

The propagation of signals from the retina to the brain is crucial for proper visual and non-visual behavior. This signal propagation is mediated by the output neurons of the retina; the retinal ganglion cell (RGC). The development of RGCs is a complex process that relies on multiple stages of overlapping but distinct developmental programs, with hierarchal transcriptional changes facilitating broad RGC pathfinding and guidance, then further specificity generated by a mixture of transcriptional regulation, activity-dependent mechanisms, and paracrine signaling. The understanding of RGC development is critical to work that seeks to regenerate the retina following injury or disease. In this thesis, I explored two distinct methods of RGC development and the classes of RGCs that are generated. Firstly, I explored the role of a novel transcription factor POU3F1, demonstrating its critical role in the formation of contralaterally projecting retinal ganglion cells. Secondly, I explored the role of glial cell exocytosis in retinal development, where I found it was crucial for the proper targeting of axons to the circadian centers of the brain and for the proper development of circadian photoentrainment. Taken together this thesis provides a comprehensive overview of two stages of development.

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OptoDrum

Applications:
12 Neurodevelopment and Circuit Mechanisms
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Development
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Glial Suppression
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Retinal Ganglion Cell Dysfunction
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Vision Science
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Cell Reports (Nov 25, 2025) Retinal glia regulate development of the circadian photoentrainment circuit

Brown TW, Vilallongue N, Hales SC, Srikanta S, Rochon PL, Rangel Olguin AG, Waxman SB, Tufford A, Van Prooijen J, Krishnaswamy A, Cermakian N, Cayouette M

DOI: 10.1016/j.celrep.2025 >>

Featured image for “Retinal glia regulate development of the circadian photoentrainment circuit”

The study shows that special support cells in the retina called Müller glia help guide the development of a circuit that lets light reset the body’s internal clock (circadian photoentrainment). Light information is sent to the brain by intrinsically photosensitive retinal ganglion cells (ipRGCs), but how these neurons form correct connections was unclear. The researchers found that during early development, Müller glia closely interact with these ipRGCs and release chemical signals like ATP that help the neurons mature properly. If this glia‑to‑neuron communication is disrupted, the light‑driven adjustment of daily rhythms is impaired, even though basic vision and pupil responses remain normal — showing that glial cells are essential for assembling the circadian light‑sensing pathway.

Circadian photoentrainment depends on intrinsically photosensitive retinal ganglion cells (ipRGCs), which convey environmental light information to the hypothalamus. While the anatomy and function of mature ipRGCs are well characterized, the mechanisms guiding their developmental integration into the circadian circuit remain unclear. Here, using transsynaptic rabies tracing in mice, we show that Müller glia are primary upstream partners of developing hypothalamus-projecting ipRGCs, suggesting a role for glia-neuron communication in the assembly of the photoentrainment pathway. We further show that disrupting SNARE function specifically in Müller glia during early postnatal development impairs ATP release, induces ipRGC hyper-responsiveness to light, and results in defective photoentrainment. In contrast, visual acuity and the pupillary light reflex, which are mediated by different RGC/ipRGC subtypes, remain unaffected. These results indicate a critical and circuit-specific role for Müller glia in shaping the development and function of the retinal pathway underlying circadian photoentrainment.

Related Products:

OptoDrum

Applications:
12 Neurodevelopment and Circuit Mechanisms
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Development
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Glial Suppression
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Vision Science
>

Advanced Science (Weinheim) (Sep 01, 2025) A High-Fidelity RNA-Targeting Cas13X Downregulates Connexin43 in Macroglia: A Novel Neuroprotective Strategy for Glaucoma

Zhao G, Li Z, Zhao MJ, Li SY, Xia Q, Xu S, Zhang Y, Wang Y, Li F, Liu YL, Guo YH, Xu RX, Zhou H, Zhou H, Ding WW, Wang YC, Miao Y, Wang Z

DOI: 10.1002/advs.202415856 >>

Featured image for “A High-Fidelity RNA-Targeting Cas13X Downregulates Connexin43 in Macroglia: A Novel Neuroprotective Strategy for Glaucoma”

In Glaucoma, ganglion cell death is mediated by activated microglia. Zhao et al found that microglia activation is aided by ATP released by macroglia, and that this release comes through connexin43 (Cx43) containing hemichannels. Using a high-fidelity RNA-targeting Cas13X (hfCas13X) system, Cx43 was selectively downregulated at the RNA level. In a chronic ocular hypertension mouse model, macroglial Cx43 knockdown reduced microglial reactivity, preserved RGC survival, and maintained optic nerve integrity. Functional analyses showed improved visual performance (measured with OptoDrum) in treated animals.

Glaucoma is a neurodegenerative disease characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, ultimately leading to irreversible vision loss. Elevated intraocular pressure (IOP) is one of the significant risk factors in glaucoma; however, neurodegeneration continues even after effective IOP management, underscoring the need for neuroprotective therapies. This study investigates the role of connexin43 (Cx43), which is extensively expressed in retinal macroglia, in regulating microglial activation and optic nerve degeneration in glaucoma. A high-fidelity CRISPR-Cas13 (hfCas13X) system is employed to selectively target and knock down Cx43 expression in macroglia. The findings reveal that Cx43-mediated ATP release through hemichannels exacerbates microglial activation and neuroinflammation, thereby contributing to RGC loss. Notably, in a mouse model of chronic ocular hypertension (COH) glaucoma, knocking down Cx43 in macroglia using the hfCas13X system significantly promoted the survival of RGCs and the integrity of the optic nerve, and improved visual function. The hfCas13X system, which offers high-fidelity RNA editing with minimal off-target effects, represents a novel and promising therapeutic strategy for glaucoma, highlighting the potential of gene editing technologies in the management of neurodegenerative diseases.

Related Products:

OptoDrum

Applications:
05 Glaucoma and Optic Nerve Neurodegeneration
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06 Retinal Degeneration and Inherited Retinal Disease
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Glaucoma
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Glial Suppression
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Neuroinflammation
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Optic Nerve Damage
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Retinal Ganglion Cell Death
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Retinal Ganglion Cell Dysfunction
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Nature Neuroscience (Jun 28, 2025) Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration

Groh J, Feng R, Yuan X, Liu L, Klein D, Hutahaean G, Butz E, Wang Z, Steinbrecher L, Neher J, Martini R, Simons M.

DOI: 10.1038/s41593-025-01955-w >>

Featured Publication

Featured image for “When Brain Defenders Turn Destructive: How Microglia and T Cells Promote Age-Related Decline”

As we get older, immune cells in the brain called microglia can become overactive and attract aggressive CD8+ T cells. These T cells then attack the brain’s axons’ protective layer, known as myelin, leading to its damage and a decline in brain function. Groh et al reveal the chain reaction behind these age-related brain changes and point to new opportunities for preventing or slowing down brain degeneration. The OptoDrum assay confirmed the link between axon degeneration and behavioral vision deficits.

Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8⁺ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial-immune interactions. Mechanistically, we show that the CXCL10-CXCR3 axis is crucial for the recruitment and retention of CD8⁺ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.

Related Products:

OptoDrum

Applications:
01 Systemic Aging and CNS decline
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02 Neuroinflammation and Autoimmune CNS Disease
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11 Ocular Inflammation and Immune-Mediated Eye Disease
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Aging
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Autoimmune Demyelinating Diseases
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Glial Suppression
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Optic Nerve Damage
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Optic Neuritis
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Retinal Ganglion Cell Death
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Cell Journal (May 28, 2023) Erythropoietin Protects against Retinal Damage in A Rat Model of Optic Neuropathy via Glial Suppression

Eghbali A, Anvarinia Y, Sanjari MS, Pakdel F, Seyedsadr M, Hosseini Mazinani F, Zare L, Zarei-Kheirabadi M, Satarian L

DOI: 10.22074/cellj.2023.1971689.1159 >>

Featured image for “Erythropoietin Protects against Retinal Damage in A Rat Model of Optic Neuropathy via Glial Suppression”

In a rat model of traumatic optic neuropathy, erythropoietin (EPO) demonstrated neuroprotective effects by safe-guarding retinal ganglion cells, reducing reactive astrocyte activation, and promoting axon regeneration. Using the OptoDrum, visual function was assessed through optomotor tests, with EPO-treated animals showing significant improvement in visual ability compared to the control group.

Objective: Traumatic optic neuropathy (TON) causes partial or complete blindness because death of irreplaceable retinal ganglion cells (RGCs). Neuroprotective functions of erythropoietin (EPO) in the nervous system have been considered by many studies investigating effectiveness of this cytokine in various retinal disease models. It has been found that changes in retinal neurons under conditions of glial cells are effective in vision loss, therefore, the present study hypothesized that EPO neuroprotective effect could be mediated through glial cells in TON model. Materials and methods: In this experiment study, 72 rats were assessed in the following groups: intact and optic nerve crush which received either the 4000 IU EPO or saline. Visual evoked potential and optomotor response and RGC number were assessed and regenerated axons evaluated by anterograde test. Cytokines gene expression changes were compared by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Density of astrocytes cells, assessed by fluorescence intensity, in addition, possible cytotoxic effect of EPO was measured on mouse astrocyte culture in vitro. Results: in vitro data showed that EPO was not toxic for mouse astrocytes. Intravenous injection of EPO improved vision, in terms of visual behavioral tests. RGCs protection was more than two times in EPO, compared to the vehicle group. More regenerated axons were determined by anterograde tracing in the EPO group compared to the vehicle. Moreover, GFAP immunostaining showed while the intensity of reactive astrocytes was increased in injured retina, systemic EPO decreased it. In the treatment group, expression of GFAP was down-regulated, while CNTF was upregulated as assessed by qRT-PCR in the 60^th day post-crush. Conclusion: Our study showed that systemic administration of EPO can protect degenerating RGCs. Indeed, exogenous EPO exerted neuroprotective and neurotrophic functions by reducing reactive astrocytic gliosis. Therefore, reduction of gliosis by EPO may be considered as therapeutic targets for TON.

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OptoDrum