Biology subjects

Michon, F.

Publications and source records attributed to Michon, F..

13 recordsLinked to original sources

bioRxiv2026

Pitx2-associated early-onset glaucoma alters corneal innervation and sensory function in a sex-specific manner

PurposePitx2-associated developmental glaucoma is characterized by anterior segment dysgenesis, ocular hypertension, and optic neuropathy. Its consequences for corneal sensory innervation remain poorly understood. We investigated whether this disease alters corneal nerve structure and sensory function in a sex-dependent manner. MethodsMale and female Pitx2egl1/egl1 and Pitx2+/+ mice were examined at 1 and 3 months. Ocular phenotyping included intraocular pressure, fundus imaging, visual evoked potentials, and optic nerve ultrastructure. RNA sequencing of corneas and trigeminal ganglia was performed at 3 months. Corneal innervation was assessed by {beta}III-tubulin immunofluorescence and volumetric quantification of nerve fibers. Corneal sensitivity was measured using Von Frey filaments. ResultsPitx2egl1/egl1 mice developed progressive ocular hypertension, fundus abnormalities, reduced visual evoked potential amplitudes, and optic nerve degeneration, supporting the model as early-onset glaucoma. Baseline sex-related transcriptional differences were limited in both cornea and trigeminal ganglia. In contrast, Pitx2 mutation induced sex-dependent molecular responses. Female corneas showed broader transcriptional changes enriched in inflammatory, stress-response, and tissue-remodeling pathways, whereas male corneas showed a more restricted response involving metabolic and homeostatic processes. Similar sex divergence was observed in trigeminal ganglia. Corneal nerve fiber volume was reduced in both sexes at 3 months but not at 1 month, whereas reduced sensitivity was detected only in mutant males. ConclusionsThis study identifies sexual dimorphism as a component of Pitx2-associated developmental glaucoma. Furthermore, our findings suggest that glaucoma affects the corneal sensory system beyond optic nerve pathology, highlighting a potentially overlooked dimension of disease relevant to ocular surface monitoring and patient management. HighlightsO_LIDisruption of the cornea-trigeminal ganglion axis with coordinated molecular and functional alterations in Pitx2-associated early-onset glaucoma C_LIO_LISex-dependent modifications in both cornea and trigeminal ganglion responses to early-onset glaucoma C_LIO_LIProgressive corneal neurodegeneration in early-onset glaucoma C_LI

neuroscience↗

bioRxiv2025

Reversible multiscale corneal sexual dimorphism orchestrates neuro-epithelial coupling and tear proteome composition

Donor-recipient sex mismatch is an under-recognized risk factor for corneal graft rejection, yet the biological underpinnings at the ocular surface remain undefined. We hypothesized that sex hormones coordinately tune the tear-nerve-epithelium axis and that androgen exposure could normalize sex-linked differences relevant to alloimmune risk. We profiled 12-week-old mice in three hormonal contexts, i.e. male, female, and testosterone-treated female, combining tear biochemistry and label-free proteomics with epithelial lineage dynamics, in vivo sensory function, and corneal/trigeminal transcriptional readouts. Tear collection rate was comparable across groups, but total tear protein was reduced in females. Proteomics revealed extensive sex differences in extracellular composition, spanning lipid transport, protease-antiprotease balance, complement activity, and secretory/mucin pathways. Epithelial analyses showed sex-linked differences in progenitor output and spatial deployment, and sensory metrics indicated divergent innervation architecture and function. Across modalities, androgen supplementation in females shifted molecular and physiological profiles toward the male state, attenuating nearly all dimorphic signals, demonstrating that close to all sexual dimorphism observed here is reversible by testosterone and reflects an actively maintained endocrine state rather than a fixed developmental program. Complementary metabolite profiling provides a sex-stratified atlas of free modified nucleosides in tears, positioning extracellular epitranscriptomic markers as accessible indicators of hormonal context. Together, these results establish a multiscale, hormone-responsive sexual dimorphism at the ocular surface and offer a mechanistic framework linking sex and endocrine status to parameters that influence graft integration. They motivate sex-aware biomarkers, stratification by hormonal context in diagnostics and trials, and therapeutic strategies, including androgenic modulation, to mitigate the elevated rejection risk associated with sex mismatch in corneal transplantation.

physiology↗

bioRxiv2025

Integrated tear proteomics define the molecular blueprint of corneal epithelial repair

The tear film plays an essential role in corneal protection and regeneration following injury. Although the cornea is a structurally conserved organ across terrestrial vertebrates, the extent to which tear film mediated wound healing responses are evolutionarily conserved remains unclear. This study aimed to identify core and species-specific molecular pathways activated in the tear film during corneal wound healing in humans and mice. We conducted a meta analysis of tear proteomic datasets from human subjects undergoing photorefractive keratectomy (PRK) and mice subjected to mechanical corneal abrasion. Differentially expressed proteins were identified and subjected to Reactome and Gene Ontology (GO) enrichment analyses to determine conserved and divergent biological responses. Approximately one third of the tear film proteomic response to corneal injury was conserved across species. Shared upregulated pathways included complement activation, actin cytoskeletal remodeling, protein synthesis, and acute inflammatory responses. Simultaneously, pathways related to adaptive immunity, proteolysis, and general metabolism were consistently downregulated. Human specific responses were enriched in secretory pathways, vesicle trafficking, and immune surveillance, whereas murine specific responses highlighted mitochondrial activation, oxidative metabolism, and stress adaptation. These distinctions reflect species dependent physiological strategies in managing epithelial repair. Our findings reveal a conserved molecular framework that governs corneal wound healing across species, with notable species specific adaptations. This cross species comparison underscores the translational relevance of tear film analysis and supports the development of targeted therapies tailored to human specific wound healing mechanisms in ocular surface disease.

physiology↗

bioRxiv2025

Temporal analysis of tear fluid proteome reveals critical corneal repair events after photorefractive surgery

Corneal epithelial wound healing is a complex and finely orchestrated process critical for restoring visual acuity following injury or surgery. Photorefractive keratectomy (PRK), a common refractive surgical procedure, provides an ideal clinical model to study this process. Here, we employed advanced proteomic analysis to comprehensively map the dynamic changes in the tear fluid proteome at distinct phases following PRK. Our findings revealed significant alterations in nearly 45% of the tear proteome, highlighting temporally distinct molecular signatures. Immediately post-injury, a robust but controlled anti-inflammatory response coincided with pronounced upregulation of protein synthesis and cellular stress-management pathways. Subsequently, at day three, the molecular landscape shifted toward sustained epithelial regeneration, extracellular matrix remodeling, and controlled inflammation resolution. By delineating these critical and temporally compartmentalized molecular events, this study identifies novel tear-based biomarkers indicative of corneal healing efficacy and provides essential insights into potential therapeutic targets for improving clinical outcomes in corneal wound healing and ocular surface disorders.

physiology↗

bioRxiv2025

Decoding the molecular complexity governing corneal wound closure in vivo

The cornea, the transparent outermost layer of the eye, possesses exceptional wound healing capabilities essential for vision preservation. The complexity of the corneal microenvironment is central to its rapid healing; however, the molecular mechanisms orchestrating this process remain poorly defined, limiting therapeutic advancements. Here, we elucidate the extensive remodeling of the corneal molecular landscape following physical injury. Multi-omics analyses--including transcriptomic, epitranscriptomic, and proteomic profiling--uncover significant induction of epithelial cell plasticity driving wound closure. Moreover, lacrimal gland ablation further suppresses Pax6 expression, highlighting its regulatory role. Our multi-omic approach uniquely reveals bilateral remodeling of the molecular environment, a phenomenon constrained by an intact tear film. Collectively, our findings identify novel molecular factors critical to corneal healing, significantly advancing the understanding of epithelial plasticity. These insights will facilitate the translation of cell plasticity research into innovative strategies for tissue and organ regeneration.

physiology↗

bioRxiv2025

Mechanistic Variability in Corneal Nerve Recovery Linked to Injury Type

The cornea, a transparent tissue covering the eye, is essential for clear vision and represents the most densely innervated tissue in the body. Its extensive sensory innervation provides both sensory perception and crucial trophic support, maintaining corneal health and integrity. Disruption of corneal innervation leads to neurotrophic keratitis (NK), a pathological condition caused by ocular injury, surgical procedures, or underlying diseases. The limited understanding of NKs pathophysiological mechanisms has hindered the development of innovative therapeutic approaches. In this study, we comparatively analyzed corneal innervation morphogenesis and regeneration across two clinically relevant injury models, highlighting both commonalities and differences among these contexts. Our results demonstrate that corneal nerve morphogenesis and maturation span approximately 13 weeks, from embryonic day 12 (E12) through three months of age. Additionally, we observed that the specification of distinct nerve fiber types coincided temporally with a significant enhancement in corneal sensitivity. Furthermore, we found that the type of innervation loss--either via axotomy or abrasion--differentially affected corneal sensitivity and epithelial cell homeostasis. Importantly, the regeneration mechanisms following injury were also distinctly dependent on the type of nerve damage sustained. Collectively, these findings underscore both the shared characteristics and unique aspects inherent in each NK model, highlighting the necessity for tailored therapeutic strategies specific to individual patterns of corneal innervation disruption.

neuroscience↗

bioRxiv2024

Inherited mitochondrial dysfunction triggered by OPA1 mutation impacts the sensory innervation fibre identity, functionality and regenerative potential in the cornea

Mitochondrial dysfunctions are detrimental to organ metabolism. The cornea, transparent outmost layer of the eye, is prone to environmental aggressions, such as UV light, and therefore dependent on adequate mitochondrial function. While several reports have linked corneal defects to mitochondrial dysfunction, the impact of OPA1 mutation, known to induce such dysfunction, has never been studied in this context. We used the mouse line carrying OPA1delTTAG mutation to investigate its impact on corneal biology. To our surprise, neither the tear film composition nor the corneal epithelial transcriptomic signature were altered upon OPA1 mutation. However, when analyzing the corneal innervation, we discovered an undersensitivity of the cornea upon the mutation, but an increased innervation volume at 3 months. Furthermore, the fibre identity changed with a decrease of the SP+ axons. Finally, we demonstrated that the innervation regeneration was less efficient and less functional in OPA1+/- corneas. Altogether, our study describes the resilience of the corneal epithelial biology, reflecting the mitohormesis induced by the OPA1 mutation, and the adaptation of the corneal innervation to maintain its functionality despite its morphogenesis defects. These findings will participate to a better understanding of the mitochondrial dysfunction on peripheral innervation.

pathology↗

bioRxiv2022

Predictive coding during action observation - an Electrocorticographic study

Predictive coding is a theoretical framework that has received much attention for its ability to generate testable hypotheses on how multiple brain regions integrate information during cognitive functions. Given relatively large sensorimotor delays, during social interactions, predicting the behavior of others is crucial to enable joint actions or provide competitive advantages. The action observation network (AON) has been extensively studied, but how information is integrated across its main nodes remains poorly understood. Here we leverage the high spatial and temporal resolution of intracranial Electrocorticography (ECoG), to characterize how the key nodes of the AON - including precentral, supramarginal and visual areas - exchange information. We found more top-down beta oscillation from precentral to supramarginal contacts during the observation of predictable actions while more bottom-up gamma oscillation from visual to supramarginal contacts were measured for unpredictable actions. These results, in line with predictive coding, provide critical evidence towards an understanding of how nodes of the AON integrate information to process the actions of others.

neuroscience↗

bioRxiv2022

Zebrafish cornea formation and homeostasis reflect robustness in camera-type eye biology, regardless of its environment

The cornea is the transparent tissue covering the camera-type eyes. This position makes this tissue prone to environmental aggressions, and physical alteration can have a drastic negative impact on sight. The current knowledge on zebrafish corneal physiology is too scarce to get an understanding on its strategy to maintain a clear sight in aquatic environment. In this study, we focus on corneal formation and maturation in zebrafish. After describing the morphological changes taking place from 3 days post fertilization to adulthood, we analyzed cell proliferation. We show that label retaining cells appear just before 1 month of age. Our cell proliferation study, combined to the study of Pax6a and krtt1c19e expression, demonstrate a long maturation process. This process ends with a solid patterning of corneal innervation. Finally, corneal abrasion wound healing process recapitulates the maturation process, via a plasticity period. Altogether, our study decipher the maturation steps of an aquatic cornea. These findings will facilitate the use of zebrafish as model of corneal physiology studies.

developmental biology↗

bioRxiv2022

AAV2/9-mediated gene transfer into murine lacrimal gland leads to a long-term targeted tear film modification

Corneal blindness is the fourth leading cause of blindness worldwide. Since the corneal epithelium is constantly renewed, non-integrative gene transfer cannot be used to treat corneal diseases. In numerous of these diseases, the tear film has been reported to be defective. Tears are a complex biological fluid secreted by the lacrimal apparatus. Their composition is modulated according to the context. For instance, after a corneal wound, the lacrimal gland secretes reflex tears, which contain specific growth factors supporting the wound healing process. In specific pathological contexts, such as dry eye diseases, the tear composition can support neither corneal homeostasis, nor wound healing. Here, we propose to use the lacrimal gland as bioreactor to produce and secrete specific factors to support corneal physiology. In this study, we used an AAV2/9-mediated gene transfer to supplement the tear film. First, we demonstrate that a single injection of AAV2/9 is sufficient to transduce all epithelial cell types of the lacrimal gland efficiently and widely. Then, we show that lacrimal gland physiology and corneal integrity are maintained after the injection of an AAV2/9-mediated nerve growth factor expression in the lacrimal gland. Remarkably, this injection induces an important and long-lasting secretion of this growth factor in the tear film. Altogether, our findings provide a new clinically applicable approach to tackle corneal blindness.

physiology↗

bioRxiv2021

Unilateral corneal insult in Zebrafish results in a bilateral cell shape and identity modification, supporting wound closure

Most of terrestrial and aquatic vertebrates are equipped with camera-type eyes, offering a focused and clear sight. This apparatus is rendered inefficient if its most superficial and transparent element, the cornea, is opaque. This structure, prone to environmental aggressions, bears excellent wound healing capabilities to preserve vision. Up to date, most of the corneal wound healing studies are made on mammals. Here, for the first time, zebrafish is used as model to study wound closure of corneal epithelium after abrasion. Our study demonstrates a swift wound closure after corneal insult. Interestingly, a unilateral wound induces a bilateral response. While cell proliferation is increased during wound closure, this parameter is not crucial, and cell rearrangements seems to be the driving force. Furthermore, we discovered a profound change in epithelial cell transcriptomic signature after abrasion, reflecting a modulation of cell identity and increase of phenotypic plasticity. The latter seems to unlock terminally differentiated cell capacities for wound healing, which could be the key for a speed up organ regeneration. Our results prove that zebrafish cornea is a powerful model to investigate, not only corneal wound healing, but ectodermal organ pathophysiology.

physiology↗

bioRxiv2020

Single-trial dynamics of hippocampal spatial representations are modulated by reward value

Reward value is known to modulate learning speed in spatial memory tasks, but little is known about its influence on the dynamical changes in hippocampal spatial representations. Here, we monitored the trial-to-trial changes in hippocampal place cell activity during the acquisition of place-reward associations with varying reward size. We show a faster reorganization and stabilization of the hippocampal place map when a goal location is associated with a large reward. The reorganization is driven by both rate changes and the appearance and disappearance of place fields. The occurrence of hippocampal replay activity largely followed the dynamics of changes in spatial representations. Replay patterns became more selectively tuned towards behaviorally relevant experiences over the course of learning. These results suggests that high reward value enhances memory retention via accelerating the formation and stabilization of the hippocampal cognitive map and enhancing its reactivation during learning.

neuroscience↗

bioRxiv2020

A Dual Reward-Place Association Task to Study the Preferential Retention of relevant Memories in Rats

Memories of past events and common knowledge are critical to flexibly adjust ones future behavior based on prior experiences. The formation and the transformation of these memories into a long-lasting form are supported by a dialog between the coordinated activity of population of neurons in the cortex and the hippocampus. Not all experiences are remembered equally well nor for equally long. It has been demonstrated experimentally in humans that memory strength positively depends on the behavioral relevance of the associated experience. Behavioral paradigms testing the selective retention of memory in rodents would enable to further investigate the neuronal mechanisms at play. We developed a novel paradigm to follow the repeated acquisition and retrieval of two contextually distinct, yet concurrently occurring, food-place associations in rats. We demonstrated the use of this paradigm by varying the amount of reward associated with the two locations. After delays of 2h or 20h, rats showed better memory performance for experiences associated with larger amount of reward. This effect depends on the level of spatial integration required to retrieve the associated location. Thus, this paradigm is suited to study the preferential retention of relevant experiences in rats.

animal behavior and cognition↗