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Cell Replacement Strategies in the Visual System: Insights from Development/ Stratégies de remplacement cellulaire dans le système visuel : perspectives de développement

Research workshop organized by Michel Cayouette and Seth Blackshaw from 1 to 6 September 2025.

Participants

Seth BLACKSHAW (Johns Hopkins University School of Medicine), Rod BREMNER (Lunenfeld Tanenbaum Research Institute – Toronto, Canada), Nadean L. BROWN (University of California, Davis – Davis, États-Unis), Michel CAYOUETTE (Institut de recherches cliniques de Montréal – Montréal, Canada), Alain CHÉDOTAL (Institut de la Vision – Paris, France), Claude DESPLAN (NYU – NEW YORK, États-Unis), Simon HIPPENMEYER (Institute of Science and Technology Austria (ISTA) – Klosterneuburg, Autriche), Caren NORDEN (Gulbenkian Institute of Molecular Medicine – Oeiras, Portugal), Muriel PERRON (Paris-Saclay Institute of Neuroscience – SACLAY, France), Birgit RITSCHKA (Research Institute of Molecular Pathology (IMP) – Wien, Autriche), Iris SALECKER (Institut de Biologie de l’Ecole Normale Supérieure – Paris, France), Karthik SHEKHAR (University of California, Berkeley – Berkeley, États-Unis), Monica VETTER (University of Utah – Salt Lake City, États-Unis), Valerie WALLACE (Donald K Johnson Eye Institute, University Health Network – Toronto, Canada), Lucie ZILOVA (Centre for Organismal Studies Heidelberg – Heidelberg, Allemagne).

Résumé

Cet atelier a réuni 15 participants (dont 20 % de jeunes chercheurs, ECR), dont des neurobiologistes du développement, des généticiens, des spécialistes de la vision et des biologistes computationnels, pour discuter des mécanismes fondamentaux du développement de la rétine et du système visuel et de leurs implications pour les stratégies de régénération. À travers divers modèles, de la drosophile et des poissons à la souris et à l’humain, les participants ont exploré comment la diversité neuronale, la progression des lignées et la plasticité cellulaire façonnent l’assemblage du système visuel et éclairent les approches de remplacement cellulaire.

Summary

This workshop brought together 15 participants (20% early-career researchers, ECR) including developmental neurobiologists, geneticists, vision scientists, and computational biologists to discuss fundamental mechanisms of retinal and visual system development and their implications for regenerative strategies. Across diverse models, from Drosophila and fish to mice and humans, participants explored how neural diversity, lineage progression, and cellular plasticity shape visual system assembly and inform cell replacement approaches.

Report 

Building diversity through temporal and spatial patterning

Claude Desplan opened the meeting with a comprehensive view of neuronal diversification in the Drosophila visual system. His work revealed how a sequential series of temporal transcription factors (tTFs) and a compact set of continuously expressed “selector” transcription factors orchestrate the generation of over 250 neuron types. This integrative framework links temporal patterning to stable neuronal identity through cis-regulatory logic, offering a generalizable blueprint for how complex neuronal repertoires arise and are maintained. Extending these principles to vertebrates, Simon Hippenmeyer presented clonal analyses in the mouse superior colliculus using MADM-based lineage tracing. His findings show that individual radial glial progenitors are multipotent and can generate both excitatory and inhibitory neurons at any point in the lineage, including at terminal divisions. The balance of these neuron types is governed by PTEN signaling, suggesting parallels between developmental control of excitation–inhibition balance and disorders such as autism. Comparing lineage behavior in the colliculus and neocortex revealed striking evolutionary differences in temporal regulation of neurogenesis.

Michel Cayouette presented complementary lineage tracing in the developing retina, demonstrating that retinal progenitors divide asymmetrically to generate diverse neuronal types, and that division orientation plays a decisive role in tissue expansion. He also introduced work identifying temporal identity factors in retinal progenitors that can reprogram adult Müller glia into neuron-like cells, highlighting developmental timing as a potential lever to stimulate regeneration. Seth Blackshaw showed how single-cell multiomics can uncover conserved gene regulatory programs driving temporal patterning of retinal cell types and how species-specific changes, exemplified by the cone-rich ground squirrel retina, reshape these networks. He also presented new mechanisms regulating injury-induced neurogenesis in Müller glia and identified multiple pathways to induce neurogenic competence in adult mammalian glia. Finally, Monica Vetter further examined the molecular logic of retinal temporal competence. Her group identified Foxp1 as a key regulator linking Polycomb-mediated repression to the transition between early and late competence states. This gene network connects chromatin remodeling, transcriptional dynamics, and the sequential production of retinal cell types.

Cell migration and tissue organization

Caren Norden discussed how diverse migration modes: somal translocation, multipolar migration, and bidirectional movements, govern retinal lamination. Her work underscores that neuronal migration is shaped not only by intrinsic programs but also by tissue-level interactions, as illustrated by bipolar cells switching between active and passive migration depending on their microenvironment. Valerie Wallace highlighted the influence of spatial organization and niche context on photoreceptor development and degeneration. She presented new genetic tools to track synaptically connected cells in vivo, aiming to understand how transplanted or regenerated neurons integrate into host circuits. Her observations emphasized the robustness and adaptability of retinal connectivity and the critical role of the tissue environment in guiding proper lamination.

Regeneration and cellular plasticity

Lucie Zilova (ECR) showcased the remarkable regenerative capacity of medaka fish retinal stem cells (RSCs). Her work using single-cell transcriptomics and fish-derived organoids demonstrates that RSC identity can be re-established after ablation, revealing intrinsic plasticity and the contribution of niche-derived cues. These organoid systems not only model in vivo neurogenesis but also expose alternative developmental trajectories, offering platforms to identify factors that sustain stemness. Muriel Perron discussed Müller glia reprogramming in Xenopus, focusing on how inflammatory signals from microglia determine regenerative competence. Her findings suggest that the microenvironment dynamically regulates whether these cues promote proliferation or neurogenesis, highlighting both the opportunities and challenges of harnessing inflammation for repair. Birgit Ritschka (ECR) explored aging and regeneration of the retinal pigment epithelium (RPE) using human stem cell–derived models. She showed that cellular senescence drives functional decline, but that clearance of senescent cells restores regenerative capacity. Complementary Xenopus studies revealed a dedifferentiation trajectory enabling RPE cells to regenerate both RPE and neuronal fates, illustrating mechanisms that could be exploited to rejuvenate aged human RPE. Finally, Karthik Shekhar (ECR) presented cross-species retinal single-cell atlases showing deep conservation of retinal cell types, including midget RGC homologs across mammals, offering insight into primate high-acuity vision and glaucoma vulnerability, with similar patterns emerging for amacrine cells. He also introduced a whole-mount spatial transcriptomics approach revealing non-uniform RGC distribution and a subset of perivascular RGCs with enhanced survival under hypoxic stress, highlighting complementary intrinsic and extrinsic neuroprotective mechanisms.

Developmental blueprints for connectivity and disease 

Iris Salecker presented how layered synaptic architecture emerges in the Drosophila optic lobe. Her genetic analyses traced a cascade of sequential repressive interactions from neuroepithelial cells to differentiated neurons that establish subtype-specific layering, offering insight into how developmental gene networks build precise connectivity maps. Alain Chédotal provided a human development perspective, using single-nucleus and spatial transcriptomics to map early retinal lineages and the emergence of ipsilateral and contralateral retinal ganglion cell projections. His data reveal molecular programs controlling visual system laterality and offer a framework for understanding congenital visual pathway defects. Nadean Brown examined in vivo mouse models manipulating Shh and Pax2 signaling during eye development. These studies connect morphogen gradients and transcription factor networks to optic nerve formation and provide new models for congenital disorders such as morning glory disc anomaly. Lastly, Rod Bremner proposed that mechanisms regulating cell cycle length profoundly influence cancer susceptibility and potentially regeneration. His team demonstrated that slowing the cycle of cancer-prone retinal cells prevents tumor formation without affecting the proportion of proliferating cells, suggesting that cell cycle kinetics are key determinants of epigenetic stability, an idea that may extend to regenerative reprogramming.

Emerging themes and perspectives 

Across species and systems, several unifying concepts emerged during the workshop. First, temporal patterning and cell cycle control are universal strategies to balance proliferation and differentiation, and both maybe exploited to stimulate visual system regeneration. Second, the niche environment, whether through PTEN signaling, inflammation, or physical interactions, profoundly influences stem cell behavior and regenerative capacity. Third, chromatin dynamics and transcriptional hierarchies underlie both developmental competence and reprogramming potential.

Together, these insights underscore that understanding development provides a conceptual and mechanistic foundation for designing cell replacement and regeneration strategies in the visual system. By bridging disciplines and model systems, the meeting fostered a collective vision for translating developmental logic into therapies that restore sight.


OpenEdition vous propose de citer ce billet de la manière suivante :
ldiebold (27 octobre 2025). Cell Replacement Strategies in the Visual System: Insights from Development/ Stratégies de remplacement cellulaire dans le système visuel : perspectives de développement. Les carnets de la Fondation des Treilles. Consulté le 15 février 2026 à l’adresse https://doi.org/10.58079/151uz