Eye Development Research Articles

Keratin 8/18a.1 Expression Influences Embryonic Neural Crest Cell Dynamics and Contributes to Postnatal Corneal Regeneration in Zebrafish.

A complete understanding of neural crest cell mechanodynamics during ocular development will provide insight into postnatal neural crest cell contributions to ophthalmic abnormalities in adult tissues and inform regenerative strategies toward injury repair. Herein, single-cell RNA sequencing in zebrafish during early eye development revealed keratin intermediate filament genes krt8 and krt18a.1 as additional factors expressed during anterior segment development. In situ hybridization and immunofluorescence microscopy confirmed krt8 and krt18a.1 expression in the early neural plate border and migrating cranial neural crest cells. Morpholino oligonucleotide (MO)-mediated knockdown of K8 and K18a.1 markedly disrupted the migration of neural crest cell subpopulations and decreased neural crest cell marker gene expression in the craniofacial region and eye at 48 h postfertilization (hpf), resulting in severe phenotypic defects reminiscent of neurocristopathies. Interestingly, the expression of K18a.1, but not K8, is regulated by retinoic acid (RA) during early-stage development. Further, both keratin proteins were detected during postnatal corneal regeneration in adult zebrafish. Altogether, we demonstrated that both K8 and K18a.1 contribute to the early development and postnatal repair of neural crest cell-derived ocular tissues.

Ultrasonic registration of myopic changes in the eye of Japanese quail chicks raised under the different spectrum of everyday illumination

Abstract High-resolution ultrasound techniques are employed in ophthalmology for detecting age-related changes in the eyeball’s structure, diagnosing tumours and vascular conditions. Meanwhile, acoustic microscopy methods are widely used in laboratory animal research. Our experiments utilised a short ultrasonic pulse (30-80 MHz) and B/Z-scan mode with dynamic focusing. This study utilised these parameters to measure various ocular dimensions, including the longitudinal and transverse size of the eyeball, the thickness of the lens, and the scleral-cornea, vitreous and chorioretinal complex. The sample comprised individuals of varying ages, an adult bird (65 days), and chicks across four age stages (10, 23, 36, 45 days), all studied in situ. The method enabled observation of age-related alterations in ocular structures throughout the ontogenesis of the animal, illuminated daily using an incandescent lamp alongside yellow and blue light filters. The outcomes illustrate that the measurement technique’s sensitivity detects an anterior-posterior axis (APA) escalation of quail eyes with an error range of ±15 microns. The method’s sensitivity adequately analysed the impact of the spectral composition of everyday lighting on deviations in eye development.

Evaluation of aspartame effects at environmental concentration on early development of zebrafish: Morphology and transcriptome1

The use of aspartame as an artificial sweetener is prevalent in a wide range of everyday food products, potentially leading to health complications such as obesity, diabetes mellitus, autism spectrum disorders, and neurodegeneration. Aspartame has also been detected in natural water bodies at a concentration of 0.49 μg/L, yet research on its ecotoxicological effects on aquatic life remains scarce. This study aimed to investigate the potential negative effects of environmentally relevant concentrations of aspartame on the development of various tissues and organs in zebrafish embryos. We used a zebrafish model to treat embryos with aspartame at environmental concentration and those higher than in the environment—up to 1000 times. We observed that after exposure to aspartame body length increased, pigmentation was delayed, and neutrophil production inhibited in zebrafish. Furthermore, transcriptome analysis revealed that early exposure of zebrafish embryos to aspartame affected the transcriptomics of various systems, primarily by downregulating genes related to immune cell production, eye and optic nerve development, nervous system development, and growth hormone-related transcription. Most of the genes associated with ferroptosis were upregulated. This study provides new insights into the ecotoxicological effects of aspartame on aquatic environments.

The Id protein Extramacrochaetae restrains the E protein Daughterless to regulate Notch, Rap1, and Sevenless within the R7 equivalence group of the Drosophila eye.

The Drosophila Id gene extramacrochaetae (emc) is required during Drosophila eye development for proper cell fate specification within the R7 equivalence group. Without emc, R7 cells develop like R1/6 cells, and there are delays and deficits in differentiation of non-neuronal cone cells. Although emc encodes an Inhibitor of DNA-binding (Id) protein that is known to antagonize proneural bHLH protein function, no proneural gene is known for R7 or cone cell fates. These fates are also independent of daughterless (da), which encodes the ubiquitous E protein heterodimer partner of proneural bHLH proteins. We report here that the effects of emc mutations disappear in the absence of da, and are partially mimicked by forced expression of Da dimers, indicating that emc normally restrains da from interfering with R7 and cone cell specification, as occurs in emc mutants. emc, and da, regulate three known contributors to R7 fate, which are Notch signaling, Rap1, and Sevenless. R7 specification is partially restored to emc mutant cells by mutation of RapGap1, confirming that Rap1 activity, in addition to Notch activity, is a critical target of emc. These findings exemplify how mutations of an Id protein gene can affect processes that do not require any bHLH protein, by restraining Da activity within physiological bounds.

Control of fate specification within the dorsal head of Drosophila melanogaster.

During development, unique combinations of transcription factors and signaling pathways carve the nascent eye-antennal disc of the fruit fly Drosophila melanogaster into several territories that will eventually develop into the compound eye, ocelli, head epidermis, bristles, antenna and maxillary palpus of the adult head. Juxtaposed patterns of Hedgehog (Hh) and Decapentaplegic (Dpp) initiate compound eye development, while reciprocal domains of Dpp and Wingless (Wg) induce formation of the antennal and maxillary palp fields. Hh and Wg signaling, but not Dpp, contribute to the patterning of the dorsal head vertex. Here, we show that combinatorial reductions of the Pax6 transcription factor Twin of Eyeless and either the Wg pathway or the Mirror (Mirr) transcription factor trigger a transformation of the ocelli into a compound eye and the neighboring head epidermis into an antenna. These changes in fate are accompanied by the ectopic expression of Dpp, which might be expected to trigger these changes in fate. However, the transformation of the field cannot be replicated by increasing Dpp levels alone despite the recreation of adjacent Hh-Dpp and Wg-Dpp domains. As such, the emergence of these ectopic organs occurs through a unique regulatory path.

A nuclear jamming transition in vertebrate organogenesis.

Jamming of cell collectives and associated rigidity transitions have been shown to play a key role in tissue dynamics, structure and morphogenesis. Cellular jamming is controlled by cellular density and the mechanics of cell-cell contacts. However, the contribution of subcellular organelles to the physical state of the emergent tissue is unclear. Here we report a nuclear jamming transition in zebrafish retina and brain tissues, where physical interactions between highly packed nuclei restrict cellular movements and control tissue mechanics and architecture. Computational modelling suggests that the nuclear volume fraction and anisotropy of cells control the emerging tissue physical state. Analysis of tissue architecture, mechanics and nuclear movements during eye development show that retina tissues undergo a nuclear jamming transition as they form, with increasing nuclear packing leading to more ordered cellular arrangements, reminiscent of the crystalline cellular packings in the functional adult eye. Our results reveal an important role of the cell nucleus in tissue mechanics and architecture.

A large-scale in vivo screen to investigate the roles of human genes in Drosophila melanogaster.

Understanding the signaling pathways in which genes participate is essential for discovering the etiology of diseases in humans. The model organism, Drosophila melanogaster, has been crucial in understanding the signaling pathways in humans, given the evolutionary conservation of a significant number of genes between the two species. Genetic screens using Drosophila are a useful way of testing large number of genes to study their function and roles within signaling pathways. We conducted a large-scale genetic screen to identify which human genes cause an alteration in the morphology of the Drosophila eye. The GMR-Gal4 was employed to activate a single UAS-human gene in the eye tissue. In total, we screened 802 UAS-human gene stocks, corresponding to 787 human protein-coding genes, for the ability to influence eye development. We found that overexpression of 64 human genes were capable of disrupting eye development, as determined by phenotypic changes in eye texture, size, shape, bristle morphology, and ommatidia organization. Subsequent analysis revealed that the fly genome encodes proteins that are homologous to a majority of the 64 human genes, raising the possibility that overexpression of these transgenes altered eye development by altering the activity of evolutionarily conserved developmental signaling pathways. Consistent with this hypothesis, a secondary screen demonstrated that overexpression of fly homologs produced phenotypes that mimicked those produced by overexpression of the human gene. Our screening has identified 64 human genes capable of inducing phenotypes in the fly, offering a foundation for ongoing research aimed at understanding functionally conserved pathways across species.

Visual toxicity in zebrafish larvae following exposure to 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), triphenyl phosphate (TPhP), and isopropyl phenyl diphenyl phosphate (IPPP)

TPhP and IPPP, alternatives to PBDEs as flame retardants, have been studied for their developmental toxicity, but their visual toxicities are less understood. In this study, zebrafish larvae were exploited to evaluate the potential ocular impairments following exposure to BDE-47, TPhP, and IPPP. The results revealed a range of ocular abnormalities, including malformation, vascular issues within the eyes, and histopathological changes in the retina. Notably, the visually mediated behavioral changes were primarily observed in IPPP and TPhP, indicating that they caused more severe eye malformations and vision impairment than BDE-47. Molecular docking and MD simulations showed stronger binding affinity of TPhP and IPPP to RAR and RBP receptors. Elevated ROS and T3 levels induced by these compounds led to apoptosis in larvae eyes, and increased GABA levels induced by TPhP and IPPP hindered retinal repair. In summary, our results indicate TPhP and IPPP exhibit severer visual toxicity than BDE-47, affecting eye development and visually guided behaviors. The underlying mechanism involves disruptions in RA signaling, retinal neurotransmitters imbalance, thyroid hormones up-regulation, and apoptosis in larvae eyes. This work highlights novel insights into the need for cautious use of these flame retardants due to their potential biological hazards, thereby offering valuable guidance for their safer applications.

Duloxetine enhances PAX6 expression and suppresses innate immune responses in murine LPS-induced corneal inflammation

Background-aimPAX6 is a key regulator of eye development and epithelial homeostasis in the cornea. When deficient, chronic corneal inflammation, neovascularization and limbal stem cell deficiency can occur. Here we investigated the potential of duloxetine, a generic serotonin reuptake inhibitor that can upregulate PAX6 in vitro, for its in vivo activity in the context of corneal inflammation. MethodsDuloxetine tolerance was tested in a human limbal stem cell line and isogenic CRISPR-knockout PAX6+/− cells. C57BL/6-Wildtype mice were administered duloxetine eye drops at concentrations of 1 μM - 2 mM and tested for toxicity and corneal PAX6 expression. In LPS-induced corneal inflammation in mice, duloxetine's effect on PAX6 expression, corneal opacification and inflammatory responses were evaluated by in vivo corneal imaging, immunostaining, and whole-transcriptome microarray analysis. ResultsNo toxicity was observed in vitro for duloxetine concentrations up to 10μΜ. In vivo, duloxetine drops were well-tolerated up to 50 μM. Duloxetine drops at 10μΜ significantly upregulated PAX6 protein levels in the cornea by 30 % within 2 days. In the LPS model, duloxetine resulted in a sustained 33 % PAX6 protein upregulation in the cornea at 7 days, and in reduced opacity within 2 days, accompanied by a significant dampening of IL-17A signaling, neutrophil degranulation, microglial activation, macrophage markers, and MMP expression, despite non-significant changes in total inflammatory cell infiltration. ConclusionShort-term administration of a repurposed generic drug, duloxetine, upregulates PAX6 protein levels in the cornea of mice and exerts an anti-inflammatory activity by dampening innate immune responses.

INFLUENCE OF TAURINE ON LARVAL EYE DEVELOPMENT AND GROWTH PERFORMANCE OF GOLDEN RABBITFISH (Siganus guttatus)

ARTICLE HIGLIGHTS- Taurine improves eye development in golden rabbitfish larvae- Enhanced growth performance with taurine-enriched rotifers- Taurine positively impacts fish eye and body growthABSTRACTGolden rabbitfish (Siganus guttatus) is an emerging species for aquaculture industry, despite constrains faced on commercial scale of seed production due to the high mortality during the first-feeding stage. An experiment was conducted to determine the effect of taurine through enrichment of rotifers as live-feed on eye development and growth performance of larval golden rabbitfish. Observation of eye development was carried out by measuring eye diameter of the larva and development of the retina based on histology assessment. Growth performance was measured for absolute growth and fin development of the larvae and survival rate. The results showed that taurine-enriched rotifer generally provided better performances for eye development and growth of larval golden rabbitfish compared with control (without taurine). Increase of taurine dose up to 0.050 g/L resulted in an increase of eye diameter, absolute growth, fin development and survival rate. Further increased increment of the taurine tended to decrease the values of the measured parameters. The eye diameter of larval golden rabbitfish fed with 0.050 g/L taurine-enriched rotifer was significantly wider (106.1±9.8 µm) (P < 0.05) compared with control (58.2±14.3 µm), but did not significantly differ from other doses of taurine (P > 0.05). Body width of larvae fed with 0.050 g/L taurine-enriched rotifer was significantly higher (127.3±14.6 µm) (P < 0.05) compared with control (98.8±18.3 µm). In regard to eye development, growth performances (total length, fin development and survival rate), dose of taurine for rotifer enrichment fed to larval golden rabbitfish Siganus guttatus was 0.050 g/L.

A possible origin of the inverted vertebrate retina revealed by physical modeling.

The evolutionary origin of the inverted retina in the vertebrate eye is unknown. This paper explores a hypothetical evolutionary scenario that explains the unique orientation of the photoreceptors in the vertebrate retina. The proposed scenario follows the scientific accepted scenario for eye evolution and gradually builds up towards an eye prototype by considering light direction detection and increase in achievable spatial resolution as the driving forces. It suggests that eye retinas developed along two different morphological processes, an evagination process that results in the inverted retina in vertebrate eyes and an invagination process that results in a verted retina in cephalopod eyes. The development of the inverted vertebrate retina and eye prototype morphology is strongly substantiated by physics of vision. The proposed evolutionary sequence for vertebrate eye development is simple and has the full potential to explain the origin of the inverted retina and leads to an eye prototype enabling visual detection and orientation. It allows the emergence of eye structures like, extraocular muscles, tapetum lucidum, biconvex lens, cornea, and pupil. This study supports the suggestion that a primitive inverted retina in the predecessor of vertebrates is of ectodermal origin and available before neurulation occurred.

Extramacrochaetae regulates Notch signaling in the Drosophila eye through non-apoptotic caspase activity.

Many cell fate decisions are determined transcriptionally. Accordingly, some fate specification is prevented by Inhibitor of DNA binding (Id) proteins that interfere with DNA binding by master regulatory transcription factors. We show that the Drosophila Id protein Extra macrochaetae (Emc) also affect developmental decisions by regulating caspase activity. Emc, which prevents proneural bHLH transcription factors from specifying neural cell fate, also prevents homodimerization of another bHLH protein, Daughterless (Da), and thereby maintains expression of the Death-Associated Inhibitor of Apoptosis (diap1) gene. We found that multiple effects of emc mutations on cell growth and on eye development were all caused by reduced Diap1 levels and corresponding activation of caspases. These effects included acceleration of the morphogenetic furrow, failure of R7 photoreceptor cell specification, and delayed differentiation of non-neuronal cone cells. Within emc mutant clones, Notch signaling was elevated in the morphogenetic furrow, increasing morphogenetic furrow speed. This was associated with caspase-dependent increase in levels of Delta protein, the transmembrane ligand for Notch. Posterior to the morphogenetic furrow, elevated Delta cis-inhibited Notch signaling that was required for R7 specification and cone cell differentiation. Thus, emc mutations reveal the importance of restraining caspase activity even in non-apoptotic cells to prevent abnormal development, in the Drosophila eye through effects on Notch signaling.

Dopaminergic amacrine cells express HCN channels in the developing and adult mouse retina.

To determine the molecular and functional expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in developing and mature dopaminergic amacrine cells (DACs), the sole source of ocular dopamine that plays a vital role in visual function and eye development. HCN channels are encoded by isoforms 1-4. HCN1, HCN2, and HCN4 were immunostained in retinal slices obtained from mice at postnatal day 4 (P4), P8, and P12 as well as in adults. Each HCN channel isoform was also immunostained with tyrosine hydroxylase, a marker for DACs, at P12 and adult retinas. Genetically-marked DACs were recorded in flat-mount retina preparation using a whole-cell current-clamp technique. HCN1 was expressed in rods/cones, amacrine cells, and retinal ganglion cells (RGCs) at P4, along with bipolar cells by P12. Different from HCN1, HCN2 and HCN4 were each expressed in amacrine cells and RGCs at P4, along with bipolar cells by P8, and in rods/cones by P12. Double immunostaining shows that each of the three isoforms was expressed in approximately half of DACs at P12 but in almost all DACs in adults. Electrophysiology results demonstrate that HCN channel isoforms form functional HCN channels, and the pharmacological blockade of HCN channels reduced the spontaneous firing frequency in most DACs. Each class of retinal neurons may use different isoforms of HCN channels to function during development. HCN1, HCN2, and HCN4 form functional HCN channels in DACs, which appears to modulate their spontaneous firing activity.

Early-life exposure to five biodegradable plastics impairs eye development and visually-mediated behavior through disturbing hypothalamus-pituitary-thyroid (HPT) axis in zebrafish larvae

Biodegradable plastics have been commonly developed and applied as an alternative to traditional plastics, which cause environmental plastic pollution. However, biodegradable plastics still present limitations such as stringent degradation conditions and slow degradation rate, and may cause harm to the environment and organisms. Consequently, in this study, zebrafish was used to evaluate the effects of five biodegradable microplastics (MPs), polyglycolic acid (PGA), polylactic acid (PLA), polybutylene succinate (PBS), polyhydroxyalkanoate (PHA) and polybutylene adipate terephthalate (PBAT) exposure on the early development, retina morphology, visually-mediated behavior, and thyroid signaling at concentrations of 1 mg/L and 100 mg/L. The results indicated that all MPs induced decreased survival rate, reduced body length, smaller eyes, and smaller heads, affecting the early development of zebrafish larvae. Moreover, the thickness of retinal layers, including inner plexiform layer (IPL), outer nuclear layer (ONL), and retinal ganglion layer (RGL) was decreased, and the expression of key genes related to eye and retinal development was abnormally altered after all MPs exposure. Exposure to PBS and PBAT led to abnormal visually-mediated behavior, indicating likely affected the visual function. All MPs could also cause thyroid system disorders, among which alterations in the thyroid hormone receptors (TRs) genes could affect the retinal development of zebrafish larvae. In summary, biodegradable MPs exhibited eye developmental toxicity and likely impaired the visual function in zebrafish larvae. This provided new evidence for revealing the effects of biodegradable plastics on aquatic organism development and environmental risks to aquatic ecosystems.

Construction and Identification of a Novel Mice Model of Microphthalmia.

Microphthalmia is a rare developmental eye disease that affects 1 in 7000 births. Currently, there is no cure for this condition. This study aimed to construct a stable mouse model of microphthalmia, thus providing a new tool for the study of the etiology of microphthalmia. The Hedgehog signaling pathway plays a crucial role in eye development. One of the key mechanisms of the Sonic Hedgehog signaling is the strong transcriptional activation ability of GLI3, a major mediator of this pathway. This study used CRISPR/Cas9 system to construct a novel TgGli3Ki/Ki lens-specific over-expression mouse line. To identify the ocular characteristics of this line, quantitative PCR, Western blot, hematoxylin and eosin staining, immunofluorescent staining, and RNA-seq were performed on the ocular tissues of this line and normal mice. The TgGli3Ki/Ki lens-specific over-expression mouse model exhibits the ocular phenotype of microphthalmia. In the TgGli3Ki/Ki mouse, Gli3 is over-expressed in the lens, and the size of the eyeball and lens is significantly smaller than the normal one. RNA-seq analysis using the lens and the retina samples from TgGli3Ki/Ki and normal mice indicates that the phototransduction pathway is ectopically activated in the lens. Immunofluorescent staining of the lens samples confirmed this activation. The TgGli3Ki/Ki mouse model consistently manifests the stereotypical microphthalmia phenotype across generations, making it an excellent tool for studying this severe eye disease. This study developed a novel animal model to facilitate clinical research on microphthalmia.

The intracellular domain of Sema6A is essential for development of the zebrafish retina.

Semaphorin6A (Sema6A) is a repulsive guidance molecule that plays many roles in central nervous system, heart and bone development, as well as immune system responses and cell signaling in cancer. Loss of Sema6A or its receptor PlexinA2 in zebrafish leads to smaller eyes and improper retinal patterning. Here, we investigate a potential role for the Sema6A intracellular domain in zebrafish eye development and dissect which phenotypes rely on forward signaling and which rely on reverse signaling. We performed rescue experiments on zebrafish Sema6A morphants with either full-length Sema6A (Sema6A-FL) or Sema6A lacking its intracellular domain (Sema6A-ΔC). We identified that the intracellular domain is not required for eye size and retinal patterning, however it is required for retinal integrity, the number and end feet strength of Müller glia and protecting against retinal cell death. This novel function for the intracellular domain suggests a role for Sema6A reverse signaling in zebrafish eye development.

Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.

Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

Combinations of β-Carotene and Taurine Enhanced Growth and Eye Development of the Golden Rabbit Fish S. guttatus

Combinations of β-Carotene and Taurine Enhanced Growth and Eye Development of the Golden Rabbit Fish S. guttatus

Embryonic and early larval development of Florida pompano, Trachinotus carolinus

AbstractThe Florida pompano, Trachinotus carolinus, is an ideal species for commercial aquaculture because of its rapid growth, tolerance to a range of environmental parameters, and high demand in the seafood market. This study detailed embryonic and early larval development of this species. Florida pompano followed similar developmental sequences to those observed in other marine teleosts, and embryos hatched between 22 and 28 h post‐fertilization. Significant brain lobe differentiation occurred prior to hatching. Pectoral fins were functional within 1‐day post‐hatch (dph). Substantial eye development occurred within 3 dph, indicating visual acuity prior to the onset of exogenous live feeding. Intestinal segments were differentiated by 3 dph, and rotifers were seen in the digestive tract by 4 dph. Digestive functions were limited through the first 7 dph because of the absence of functional gastric glands and gastric mucous cells in the rudimentary stomach, lipid vacuoles in the anterior intestines, and the persistence of acidophilic supranuclear vesicles in the posterior intestines. Within 7 dph, the pharyngeal arches differentiated, and hematopoietic tissue and mesonephric tubules were visible in the larval kidney. Their rapid larval development and organogenesis are additional factors that make Florida pompano an ideal species for aquaculture production and should encourage continued efforts toward commercialization.

Circadian disruption reduces MUC4 expression via the clock molecule BMAL1 during dry eye development

Circadian disruption, as a result of shiftwork, jet lag, and other lifestyle factors, is a common public health problem associated with a wide range of diseases, such as metabolic disorders, neurodegenerative diseases, and cancer. In the present study, we established a chronic jet lag model using a time shift method every 3 days and assessed the effects of circadian disruption on ocular surface homeostasis. Our results indicated that jet lag increased corneal epithelial defects, cell apoptosis, and proinflammatory cytokine expression. However, the volume of tear secretion and the number of conjunctival goblet cells did not significantly change after 30 days of jet lag. Moreover, further analysis of the pathogenic mechanism using RNA sequencing revealed that jet lag caused corneal transmembrane mucin deficiency, specifically MUC4 deficiency. The crucial role of MUC4 in pathogenic progression was demonstrated by the protection of corneal epithelial cells and the inhibition of inflammatory activation following MUC4 replenishment. Unexpectedly, genetic ablation of BMAL1 in mice caused MUC4 deficiency and dry eye disease. The underlying mechanism was revealed in cultured human corneal epithelial cells in vitro, where BMAL1 silencing reduced MUC4 expression, and BMAL1 overexpression increased MUC4 expression. Furthermore, melatonin, a circadian rhythm restorer, had a therapeutic effect on jet lag-induced dry eye by restoring the expression of BMAL1, which upregulated MUC4. Thus, we generated a novel dry eye mouse model induced by circadian disruption, elucidated the underlying mechanism, and identified a potential clinical treatment.