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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
>

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
·
Development
·
Glial Suppression
·
Vision Science
>

Human Molecular Genetics (Dec 15, 2023) Divergent phenotypes in constitutive versus conditional mutant mouse models of Sifrim-Hitz-Weiss syndrome

Larrigan S, Joshi SV, Mattar P

DOI: 10.1093/hmg/ddad157 >>

Featured image for “Divergent phenotypes in constitutive versus conditional mutant mouse models of Sifrim-Hitz-Weiss syndrome”

This study describes phenotypic differences between constitutive and conditional mutant mouse models of Sifrim-Hitz-Weiss syndrome, an intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. Behavioral and organic deficits depended on the location and timing of the loss-of-function mutation of CHD4, resulting in unexpected phenotypic divergence. Behavioral tests characterized the deficits of these mice. As many of these tests were vision-based, Larrigan et al used the OptoDrum to establish that these mice did not have any obvious visual deficits.

Chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), however, their functions during brain development are not fully understood. Here, we focused on Sifrim-Hitz-Weiss Syndrome (SIHIWES)-an intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. We utilized mouse genetics to excise the Chd4 ATPase/helicase domain-either constitutively, or conditionally in the developing telencephalon. Conditional heterozygotes exhibited no change in cortical size and cellular composition and had only subtle behavioral phenotypes. Telencephalon-specific conditional knockouts had marked reductions in cortical growth, reduced numbers of upper-layer neurons, and exhibited alterations in anxiety and repetitive behaviors. Despite the fact that whole-body heterozygotes exhibited comparable growth defects, they were unaffected in these behaviors, but instead exhibited female-specific alterations in learning and memory. These data reveal unexpected phenotypic divergence arising from differences in the spatiotemporal deployment of loss-of-function manipulations, underscoring the importance of context in chromatin remodeller function during neurodevelopment.

Related Products:

OptoDrum

Applications:
07 Rare and Inherited CNS and Eye Disorders
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12 Neurodevelopment and Circuit Mechanisms
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Chromatin Remodelling
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Development
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Rare Disease
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Sifrim-Hitz-Weiss syndrome
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(Nov 22, 2023) Assessment of Visual Function and Retinal Histology in a Snf2h Knockout Mouse Model

Cheng S

DOI: 10.20381/ruor-29854 >>

Featured image for “Assessment of Visual Function and Retinal Histology in a Snf2h Knockout Mouse Model”

This study investigates the role of Snf2h, an ATP-dependent chromatin remodeling protein, in retinal development and function. Conditional knockout mice lacked Snf2h in the retina from embryonic day 10.5. Visual function and retinal structure were assessed in these animals at various time points up to six months of age. Snf2h-deficient mice experienced significant visual impairment and retinal neuron loss compared to control littermates, highlighting the essential role of Snf2h in maintaining retinal structure and function. The OptoDrum provided objective data on the mice’s visual acuity. This contributed to quantifying the decline in visual function in Snf2h knockout mice over time.

Regulation of gene expression is required for embryogenesis and maintenance of the highly specialized and diverse neuron populations of the retina. Chromatin remodelling proteins control gene expression by modifying chromatin structure and are essential for many biological processes including mammalian development. The ATP-dependent chromatin remodelling protein Snf2h is highly expressed in the central nervous system, and pathogenic variants that cause neurodevelopmental abnormalities in the human population have recently been identified. This work aims to characterize the effects of Snf2h loss in the retina. Snf2h retinal conditional knockout (cKO) mice were generated using Snf2h-floxed mice and Chx10-Cre retina-specific Cre driver lines to ablate the Snf2h protein from the retina at embryonic day 10.5. Visual function was assessed via optomotor response-based testing and full-field scotopic electroretinography, and histological changes were examined via immunohistochemistry. Disease progression was tracked at one, two, three, and six months of age. Snf2h cKO mice showed a significant decline in visual function and exhibited retinal neuron loss compared to wildtype control littermates at all time points assessed. This work shows that the chromatin remodelling protein Snf2h plays an essential role in the structure and function of the retina.

Related Products:

OptoDrum

Applications:
07 Rare and Inherited CNS and Eye Disorders
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12 Neurodevelopment and Circuit Mechanisms
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Chromatin Remodelling
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Development
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Rare Disease
·
Retinal Degeneration
>

eNeuro (Apr 11, 2023) Off Starburst Amacrine Cells in the Retina Trigger Looming-Evoked Fear Responses in Mice

Bohl JM, Gope J, Sharpe ZJ, Shehu A, Garrett A, Koehler CC, Hellmer CB, Ichinose T

DOI: 10.1523/ENEURO.0183-22.2023 >>

Featured image for “Off Starburst Amacrine Cells in the Retina Trigger Looming-Evoked Fear Responses in Mice”

Looming dark stimuli (an expanding shadow) evoke evolutionary conserved fear or flight responses. This study looked at the effects on this behavior of ablating starburst amacrine cells, a specific interneuron in the retina which is involved in direction-selective retinal responses. Bohl et al found that looming-induced fear responses were eliminated when a sufficient number of OFF starburst cell were ablated. As a further behavioral readout to confirm successful starburst ablation, Bohl et al used measurements of the optomotor reflex which is known to depend on the direction-selective circuitry in the retina. OMR seemed to depend mostly on ON starburst cells, so that the two behavioral changes (OMR and looming-induced fear response) did not coincide in all mice.

A rapidly approaching dark object evokes an evolutionarily conserved fear response in both vertebrates and invertebrates, young to old. A looming visual stimulus mimics an approaching object and triggers a similarly robust fear response in mice, resulting in freeze and flight. However, the retinal neural pathway responsible for this innate response has not been fully understood. We first explored a variety of visual stimuli that reliably induced these innate responses, and found that a looming stimulus with 2-d acclimation consistently evoked fear responses. Because the fear responses were triggered by the looming stimulus with moving edges, but not by a screen flipping from light to dark, we targeted the starburst amacrine cells (SACs), crucial neurons for retinal motion detection. We used intraocular injection of diphtheria toxin (DT) in mutant mice expressing diphtheria toxin receptors (DTR) in SACs. The looming-evoked fear responses disappeared in half of the DT-injected mice, and the other mice still exhibited the fear responses. The optomotor responses (OMRs) were reduced or eliminated, which occurred independent of the disappearance of the fear responses. A histologic examination revealed that ON SACs were reduced in both mouse groups preserved or absent fear responses. In contrast, the number of OFF SACs was different among two groups. The OFF SACs were relatively preserved in mice exhibiting continued fear responses, whereas they were ablated in mice lacking fear response to looming stimulation. These results indicate that OFF SACs and the direction-selective pathway in the retina play a role in looming-induced fear behaviors.

Related Products:

OptoDrum

Applications:
12 Neurodevelopment and Circuit Mechanisms
·
Development
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Looming-Evoked Fear Responses
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Vision Science
>

Neuron (Jan 04, 2023) CyclinD2-mediated regulation of neurogenic output from the retinal ciliary margin is perturbed in albinism

Slavi N, Balasubramanian R, Lee MA, Liapin M, Oaks-Leaf R, Peregrin J, Potenski A, Troy CM, Ross ME, Herrera E, Kos-midis S, John SWM, Mason CA

DOI: 10.1016/j.neuron.2022.10.025 >>

Featured Publication

Featured image for “Unveiling the Mysteries of Albinism: Disrupted Retinal Harmony Due to CyclinD2 Deficiency”

This article is an in-depth investigation of molecular alterations underlying chiasmatic misrouting in the albino binocular circuit. During development, in a specialized retinal niche—the ciliary margin—fewer cells express the cellcycle regulator CyclinD2. Consequently, the cell cycle is elongated, resulting in fewer ipsilaterally projecting RGCs and perturbed binocular vision.

In albinism, aberrations in the ipsi-/contralateral retinal ganglion cell (RGC) ratio compromise the functional integrity of the binocular circuit. Here, we focus on the mouse ciliary margin zone (CMZ), a neurogenic niche at the embryonic peripheral retina, to investigate developmental processes regulating RGC neurogenesis and identity acquisition. We found that the mouse ventral CMZ generates predominantly ipsilaterally projecting RGCs, but this output is altered in the albino visual system because of CyclinD2 downregulation and disturbed timing of the cell cycle. Consequently, albino as well as CyclinD2-deficient pigmented mice exhibit diminished ipsilateral retinogeniculate projection and poor depth perception. In albino mice, pharmacological stimulation of calcium channels, known to upregulate CyclinD2 in other cell types, augmented CyclinD2-dependent neurogenesis of ipsilateral RGCs and improved stereopsis. Together, these results implicate CMZ neurogenesis and its regulators as critical for the formation and function of the mammalian binocular circuit.

Related Products:

OptoDrum

Applications:
07 Rare and Inherited CNS and Eye Disorders
·
12 Neurodevelopment and Circuit Mechanisms
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Albino Visual System
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Development
>

Frontiers in Cell and Developmental Biology (Nov 06, 2020) Abundant Neural circRNA Cdr1as Is Not Indispensable for Retina Maintenance

Chen XJ, Li ML, Wang YH, Mou H, Wu Z, Bao S, Xu ZH, Zhang H, Wang XY, Zhang CJ, Xue X, Jin ZB

DOI: 10.3389/fcell.2020.565543 >>

Featured image for “Abundant Neural circRNA Cdr1as Is Not Indispensable for Retina Maintenance”

The role of circular RNAs is not well understood, including Cdr1as, which is abundant in vertebrate retina. Chen et al show that CDR1as-KO mice had only minor deficits. Those included reduced contrast sensitivity, as measured with our OptoDrum. Overall, however, Cdr1as abundance is not required for retinal development and maintenance.

Cdr1as is the abundant circular RNA (circRNA) in human and vertebrate retinas. However, the role of Cdr1as in the retina remains unknown. In this study, we aimed to generate a Cdr1as knockout (KO) mouse model and investigate the retinal consequences of Cdr1as loss of function. Through in situ hybridization (ISH), we demonstrated that Cdr1as is mainly expressed in the inner retina. Using CRISPR/Cas9 targeting Cdr1as, we successfully generated KO mice. We carried out ocular examinations in the KO mice until postnatal day 500. Compared with the age-matched wild-type (WT) siblings, the KO mice displayed increased b-wave amplitude of photopic electrophysiological response and reduced vision contrast sensitivity. Through small RNA profiling of the retinas, we determined that miR-7 was downregulated, while its target genes were upregulated. Taken together, our results demonstrated for the first time that Cdr1as ablation led to a mild retinal consequence in mice, indicating that Cdr1as abundance is not indispensable for retinal development and maintenance.

Related Products:

OptoDrum

Applications:
12 Neurodevelopment and Circuit Mechanisms
·
Development
>

Human Molecular Genetics (Apr 15, 2020) Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations

Eckhardt J, Bachmann C, Benucci S, Elbaz M, Ruiz A, Zorzato F, Treves S

DOI: 10.1093/hmg/ddaa056 >>

Featured image for “Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations”

Human congenital myopathies are most commonly caused by mutations in the RYR1 gene, encoding for a muscular calcium channel. In a corresponding mouse model, this study investigates the molecular basis of the eye muscle phenotype which is part of the congenital myopathy. In the mutants, the altered calcium homeostasis and reduced calcium released by muscle fibres in the extraocular muscles lead to reduced activity of the eye muscles during development. This causes mis-expression of Myelin heavy chain (MyHC) isoforms, lack of the isoform MyHC-EO, myofibrillar disorganization, displacement and decreased number of mitochondria.

Mutations in the RYR1 gene are the most common cause of human congenital myopathies, and patients with recessive mutations are severely affected and often display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle (EOM) involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for Ryr1 mutations. Ex vivo force production in EOMs from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared with that observed in wild-type, single heterozygous mutant carriers or homozygous RyR1p.A4329D mice. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle-specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the EOM phenotype caused by the RyR1p.Q1970fsX16+p.A4329D compound heterozygous Ryr1 mutations is complex and due to a combination of modifications including a direct effect on the macromolecular complex involved in calcium release and indirect effects on the expression of myosin heavy chain isoforms.

Related Products:

OptoDrum

Applications:
07 Rare and Inherited CNS and Eye Disorders
·
Congenital Myopathy
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Development
·
Rare Disease
>