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PubMed2026

Studies on functional differentiation of xpr1a and xpr1b genes in zebrafish.

Xenotropic and polytropic retrovirus receptor 1 (XPR1) is known to be involved in various biological processes, including phosphate homeostasis, cellular signaling, brain and vascular mineralization, whereas its specific contribution to bone development remains incompletely characterized. Due to genome duplication in teleosts, zebrafish Danio rerio possess two paralogous genes of XPR1 namely xpr1a and xpr1b, whose functional divergence remains unclear. The amino acid sequence similarity between zebrafish xpr1a and xpr1b was 83.26%. In situ hybridization demonstrated overlapping localization in the head and spinal cord at 24-48 hpf, while diverged by 72 hpf, with xpr1a becoming restricted to the head while xpr1b persisted in both regions. CRISPR/Cas9 was used to generate xpr1a and xpr1b mutants. The xpr1a mutants are comparatively healthy, viable but with mild growth reduction, whereas the xpr1b mutants display high mortality, reduced body length and severe vertebral deformities. Interestingly, all the double mutants died at the embryonic stage. Moreover, to further investigate the molecular and regulatory mechanisms, we conducted comparative transcriptome analysis on bone and brain tissues from xpr1b+/+ and xpr1b-/- zebrafish. In bone tissue, 6749 DEGs were identified, comprising 3846 upregulated and 2903 downregulated genes. These DEGs were mainly enriched in the MAPK signaling pathway, Wnt signaling pathway, cysteine and methionine metabolism, and ECM-receptor interaction. RT-qPCR validated results showed that seven osteogenesis-related genes (col1a1a, sp7, runx2b, col1a2, col1a1b, alp1 and entpd5), and two phosphate homeostasis related genes (slc20a2 and pdgfba), which are essential for skeletal mineralization and phosphate homeostasis, exhibited significantly downregulated expression in bone tissue of xpr1b mutant zebrafish. These results highlight the pivotal role of xpr1b in regulating skeletal mineralization and phosphate metabolism, thereby elucidating the functional specialization of XPR1 paralogs while providing a theoretical basis for understanding bone developmental mechanism in teleost vertebrates.

Animals↗
PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals↗
PubMed2026

Development of the zebrafish foveal analogue: a quantitative atlas of high-acuity zone growth and retinal regionalisation.

The vertebrate retina contains specialised regions for high-acuity vision, exemplified by the human fovea and its zebrafish analogue, the high-acuity zone (HAZ). Despite the widespread use of zebrafish to model retinal disease, a stage-resolved quantitative reference describing normal eye, photoreceptor layer (PRL) and lens growth has been lacking. Here, we apply contrast-enhanced micro-computed tomography (micro-CT) to construct the first three-dimensional micro-CT normative atlas of wild-type zebrafish eye development across five larval stages [3, 5, 7, 10 and 18 days post-fertilisation (dpf)], mapping circumferential PRL thickness, eye and lens morphology, and compartment growth rates. Regional PRL thickening within the temporo-ventral region of the expected HAZ emerged by 5 dpf and was sustained by a localised redistribution of growth, persisting and extending towards the optic nerve through 18 dpf. The PRL, lens and eye grew through four phases, alternating between disproportionate PRL expansion and coordinated growth, while the eye remodelled from a nasal-dominant to a temporo-ventral-dominant form. This regional specialisation was protracted relative to gross ocular growth and could proceed independently of it, paralleling the extended postnatal maturation of the human fovea. This atlas provides a quantitative baseline for distinguishing disease-induced changes from normal variation, supporting zebrafish models of foveal hypoplasia and related disorders.

Animals↗
PubMed2025

Uncovering parental exposure risks of TCPP: Impaired development and metabolic homeostasis in zebrafish offspring.

As brominated flame retardants are phased out, tris (1‑chloro-2-propyl) phosphate (TCPP), a phosphorus-based flame retardant, has emerged as a prominent detectable flame retardant in the environment. However, TCPP has been found to exhibit endocrine-disrupting effects on organisms, raising significant safety concerns. In our study, we utilized the zebrafish model to explore the toxic effects of parental TCPP exposure on offspring and uncover its regulatory mechanisms through metabolomics analysis. Moreover, the impact on the nervous system and lipid metabolism was examined through behavioral analysis and specific staining. Our findings demonstrated that both embryonic and parental TCPP exposure induced developmental disorders in larvae, along with decreased locomotor activity and disordered lipid metabolism homeostasis. Parental exposure to TCPP, exhibiting stronger developmental toxicity than direct embryonic exposure, notably led to reductions in crucial energy substrates such as amino acids and carbohydrates. Meanwhile, embryonic TCPP exposure primarily affected the endogenous lipid-related metabolites including phospholipids, lipid-soluble vitamins, steroids and fatty acids, promoting lipid accumulation in larval liver and subcutaneous tissue. What's more, continuously parental and embryonic exposure showed the most pronounced effects on zebrafish development and metabolic regulation. Our study highlights the risk posed by parental exposure to TCPP on offspring zebrafish, underscoring the need for comprehensive consideration of the impact from parental exposure in pollutants regulation.

Animals↗
PubMed2026

A User-Friendly Protocol for Microinjection into Teleost Embryos to Study Gene Function.

Zebrafish (Danio rerio) and medaka (Oryzias latipes) are popular teleost models used in developmental biology and functional genomics. To achieve high-quality and reproducible microinjections, it is essential to have robust protocols for breeding, egg collection, and the precise delivery of genetic material. In this protocol, we present a comprehensive and optimized methodology for setting up breeding tanks under controlled photoperiod conditions to maximize egg yield while minimizing contamination. We provide detailed procedures for sex identification, pair selection, the use of grated breeding inserts, and methods to increase egg collection efficiency. We outline procedures for making injection gel beds, pulling needles, and calibration using one-microliter microcapillaries to achieve consistent nanoliter-scale injections. Our protocol outlines settings for the pico-liter injector that are optimized to deliver a precise amount per pulse with minimal variability. Finally, we demonstrate the application of these methods for gene knockdown using morpholino antisense oligonucleotides, gene knockout using CRISPR-Cas9, and gain-of-function mRNA overexpression experiments. Phenotypic assessments conducted at various developmental stages to evaluate gene-specific effects reveal consistent phenotypic outcomes between the morpholino and CRISPR-Cas9 approaches. This easy and comprehensive protocol enables efficient, precise, and scalable genetic manipulation of zebrafish and medaka embryos, thereby supporting advanced functional studies in developmental biology and disease modeling. To our knowledge, this is the first unified protocol for both zebrafish and medaka microinjection systems achieving 97.7% phenotype penetrance in CRISPR-Cas9 knockouts with precision together with a triple validation approach that confirms gene function across multiple techniques.

Animals↗
PubMed2026

Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar development.

Genome-wide association studies (GWAS) have identified numerous loci for insomnia, yet functional validation of effector genes remains limited because most risk variants lie in noncoding regions, and the true causal gene is not known. Here, we use prior human cell-based variant-to-gene mapping to nominate six insomnia effector genes and test them in zebrafish, a tractable diurnal vertebrate model well suited for sleep phenotyping. Our CRISPR-based behavioral screening identifies the MEIS1 ortholog, meis1b, as a regulator of sleep maintenance, with crispants displaying impaired nighttime-specific sleep maintenance and increased sleep latency. Comparative chromatin analyses reveal conserved regulatory architecture spanning the human insomnia-associated locus and selectively implicate meis1b, whereas the duplicated ohnolog meis1a was dispensable. Developmental profiling further shows that meis1b is expressed in cerebellar granule progenitors, paralleling human MEIS1 expression, and that its disruption impairs cerebellar development. Together, these findings establish zebrafish as an efficient vertebrate platform for functional interrogation of GWAS candidates and support an evolutionarily conserved cerebellar role for MEIS1 in sleep maintenance.

Animals↗
PubMed2026

TNFα-dependent modulation of WT1-MMP9 regulatory axis links developmental and inflammatory pathways in glaucoma.

Glaucomas are heterogeneous optic neuropathies associated with extracellular matrix dysregulation, abnormal ocular morphogenesis, and inflammatory signaling. Targeted deep sequencing of 586 primary congenital glaucoma (PCG) cases and 1,757 controls identified rare pathogenic variants in multiple genes, including WT1 and MMP9. Notably, WT1 variants clustered within the nuclear export sequence. Further, functional analyses showed that combined wt1-pax6 suppression in zebrafish disrupted ocular morphogenesis, highlighting developmental interdependence. In human trabecular meshwork cells, WT1 acted as a transcriptional repressor of MMP9, while TNF-α signaling triggered nitric oxide-dependent nuclear export of WT1, resulting in delayed MMP9 upregulation. This effect was reversible by inhibiting nuclear export or nitric oxide synthase. A patient-derived mutation in the nuclear-export region of WT1, disrupted this regulatory switch, causing abnormal MMP9 expression. These findings position WT1 as an important regulator linking developmental and inflammatory mechanisms in glaucoma pathogenesis.

anterior segment dysgenesis↗
PubMed2026

Discovery of NAT-6-321056 as a novel modulator of VEGFR2 signaling to suppress tumor angiogenesis.

Vascular endothelial growth factor receptor 2 (VEGFR2) is a master regulator of angiogenesis and cancer progression. However, current VEGFR2 modulators face significant challenges, including off-target toxicity and acquired resistance, underscoring the urgent need for novel therapeutic agents with improved efficacy and safety profiles. Here, we reported that virtual screening of 39,442 natural products from the ZINC natural products-derived library, coupled with molecular docking and molecular dynamics (MD) simulations to evaluate the binding stability of candidate compounds, identified NAT-6-321056 as a highly promising modulator of VEGFR2 signaling. Biological evaluations demonstrated that NAT-6-321056 exerted potent inhibition on the growth of a broad spectrum of cancer cells, including both solid tumors and hematological malignancies. In EA.hy 926 endothelial cells and SK-N-DZ neuroblast cells, the compound significantly suppressed proliferation, migration, and invasion. Microscale thermophoresis (MST) confirmed direct binding of NAT-6-321056 to VEGFR2 with favorable affinity. Kinase profiling against a panel of 33 kinases indicated that NAT-6-321056 exhibited a multi-kinase modulation profile. Mechanistic studies revealed that NAT-6-321056 suppressed the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and was associated with reduced VEGFR2 phosphorylation and attenuation of the downstream ERK/JNK/AKT signaling pathways. Moreover, NAT-6-321056 exhibited robust in vivo anti-angiogenic effects in both the chick chorioallantoic membrane (CAM) assay and transgenic zebrafish vascular fluorescence imaging models. Computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction suggested acceptable drug-like properties. Collectively, these findings demonstrated that NAT-6-321056 is a promising modulator of VEGFR2 signaling with potent anti-angiogenic activity and represents a viable candidate for cancer therapy.

Vascular Endothelial Growth Factor Receptor-2↗
PubMed2026

Are there any common effects in preclinical models of micro- and nanoplastic (MNP) exposure? A systematic review.

Micro- and nanoplastics (MNPs) are emerging contaminants detected in food sources and the marine food chain, raising concerns about human health. Although no causal relationship has been established between MNP exposure and specific diseases, growing evidence suggests adverse developmental, behavioral, cognitive and biochemical effects. This systematic review synthesized evidence from common preclinical neurotoxicology models, including C. elegans, D. rerio, D. melanogaster, in vitro systems and rodents, to identify convergent developmental, behavioral and biochemical outcomes. The protocol was preregistered in OSF, followed PRISMA-P guidelines, applied PICOS criteria, and assessed methodological quality using the European Commission's ToxRTool. Overall, 185 studies were included. Consistent findings showed impaired survival and disrupted development across all models. Behavioral alterations affecting anxiety, memory, learning, sociability and locomotor activity were also consistently reported. In addition, numerous studies identified disruptions in the serotonergic (5-HT) system, including changes in neurotransmitter levels, transporters and metabolic enzymes. Despite methodological heterogeneity, these findings indicate that MNP exposure produces reproducible neurodevelopmental and neurochemical alterations across experimental models. Future studies should improve methodological harmonization, strengthen cross-model comparability and identify robust biomarkers and key mechanisms underlying MNP-induced neurotoxicity, facilitating translation to human health risk assessment frameworks.

Animals↗
PubMed2026

Comparative Transcriptomics Reveals Shared Downstream Pathways in Craniofacial Pathology.

Treacher Collins syndrome and Nager syndrome are craniofacial developmental disorders caused by defects in ribosome biogenesis and RNA splicing, respectively, yet they exhibit overlapping abnormalities affecting neural crest cell-derived craniofacial structures. To investigate shared downstream pathogenic mechanisms, we performed a comparative transcriptomic analysis of zebrafish polr1c and sf3b4 mutant models from our previous studies. Comparative analysis identified 17 shared differentially expressed genes (DEGs) between polr1c and sf3b4 mutants, with the majority of shared genes dysregulated in the same direction, indicating a coordinated rather than random transcriptional response. Gene ontology analysis identified ATP-dependent protein folding chaperone activity as the only shared molecular function, driven in part by upregulation of hsp90aa1.2, indicating a common proteostasis response. Because chaperone activity is linked to extracellular matrix (ECM) protein processing, we cross-referenced DEGs from both mutants against the curated zebrafish matrisome. Three of the 17 shared DEGs (serpinh1b, il11a, and lepa) were matrisome-associated and upregulated in both mutants. Serpinh1b, a collagen-specific chaperone, was strongly expressed in craniofacial cartilage and mesenchymal populations during pharyngeal arch development and exhibited nearly identical fold changes in both mutants. Il11a is of particular interest because its receptor, IL11RA, is known to be associated with human craniosynostosis, suggesting potential relevance to craniofacial development. Together, it is possible to hypothesize that shared chaperone-associated transcriptional changes, together with altered ECM-related gene expression, may contribute to polr1c- and sf3b4-associated craniofacial disorders, warranting further functional validation.

Extracellular Matrix↗
PubMed2026

Integrative analysis of transcriptome and DNA methylome dynamics during caudal fin regeneration in silver pomfret (Pampus argenteus).

Caudal fin regeneration in teleost fish is a complex, multi-stage process involving coordinated molecular and cellular changes. While the role of epigenetic regulation particularly DNA methylation has been studied in model freshwater species such as zebrafish, its contribution to regeneration in marine teleosts remains largely unexplored. In this study, we integrated transcriptomic and DNA methylomic data to characterize the temporal dynamics of gene expression and methylation during caudal fin regeneration in the silver pomfret (Pampus argenteus). Using RNA-sequencing and reduced representation bisulfite sequencing (RRBS) at three biologically critical time points 1, 3, and 7 days post-amputation (dpa), we characterized the spatiotemporal molecular landscape of caudal fin regeneration. These time points capture the key transitional phases of wound healing and inflammation (1 dpa), blastema formation and progenitor proliferation (3 dpa), and regenerative outgrowth with tissue remodeling (7 dpa), enabling robust detection of the major molecular programs underlying epimorphic regeneration. Concurrently, CG-methylome analysis identified thousands of dynamically changing differentially methylated regions (DMRs). A strong global inverse correlation was observed between promoter methylation and gene expression. Integrative analysis pinpointed key regeneration genes (fgf20a, msxb, sox9b) whose expression was associated with dynamic methylation changes in their promoters or gene bodies. We conclude that DNA methylation is a dynamic and key regulatory layer that acts in concert with transcriptional reprogramming to coordinate tissue regeneration, providing new insights into the epigenetic mechanisms underlying complex regenerative processes in teleosts.

Animals↗
PubMed2026

Identification and functional characterization of a novel antiviral chicken interferon-υ.

Interferons are critical mediators of antiviral immunity in vertebrates. While type IV interferon (IFN-υ) has been identified in fish and amphibians, its existence and function in chickens remained unknown. Through systematic genomic screening, we identified and cloned a novel chicken interferon gene, designated ChIFN-υ. Phylogenetic analysis placed ChIFN-υ within a distinct clade alongside zebrafish and clawed frog IFN-υ, confirming its identity as a type IV interferon, with minimal homology to classical type I, II, or III IFNs. Expression profiling revealed constitutive ChIFN-υ expression in mucosal and immune tissues of healthy chickens, exhibiting a distinct developmental shift: highest in trachea and small intestine in 1-day-old chicks, shifting to spleen and lung in 4-week-old chickens. ChIFN-υ expression was strongly upregulated following H9N2 AIV infection. Functionally, recombinant ChIFN-υ protein activated the interferon-stimulated response element (ISRE) and Mx promoter in a dose-dependent manner and significantly inhibited the replication of both vesicular stomatitis virus (VSV) and H9N2 AIV in DF-1 cells. In vivo, early treatment with exogenous ChIFN-υ significantly reduced pulmonary and tracheal viral loads and decreased oropharyngeal and cloacal virus shedding in H9N2-infected chickens. In conclusion, this study identifies and functionally characterizes the type IV interferon in chickens, elucidating the evolutionary status, regulated expression, and antiviral efficacy of ChIFN-υ. These findings highlight its potential as a candidate for developing interferon-based therapies against avian viral diseases.

Animals↗
PubMed2026

Genome-wide identification, structural characterization, and evolutionary analysis of growth-related gene families in African catfish (Clarias gariepinus).

The somatotropic axis encompassing growth hormone (GH), insulin-like growth factor (IGF), myostatin (MSTN), and prolactin (PRL) signalling cascades is the master regulator of somatic growth, metabolism, and development in vertebrates. African catfish (Clarias gariepinus), a commercially pivotal aquaculture species, now possesses a chromosome-level reference genome (CGAR_prim_01v2); however, a systematic, genome-wide characterization spanning all five interconnected growth-related gene families has not previously been undertaken in this species. Here, we identified and characterized 15 growth-related genes spanning gh1, ghra, ghrb, Igf1, Igf2a, Igf2b, igf1ra, Igf1rb, Igf2r, Mstna, Mstnb, prl, prlra, prlrb, and smtlb distributed across 13 chromosomes. Complete one-to-one orthology with zebrafish confirmed strong dosage-balance conservation across >120 million years of teleost divergence. Physicochemical analysis resolved a clear biochemical dichotomy between compact, basic secreted ligands (19.88-45.81 kDa; pI up to 10.02) and large, acidic, heavily glycosylated membrane receptors (56.82-270.80 kDa; pI 4.85-5.97). Phylogenetic analysis confirmed 3R whole-genome duplication origins for all paralog pairs, while synteny analysis revealed a disruption of the ancestral gh1-prl chromosomal block in C. gariepinus, a finding that warrants further comparative and functional investigation. This genomic atlas provides the sequence and structural information including exon-intron boundaries, domain architecture, and chromosomal coordinates needed as a prerequisite for future marker-assisted selection and CRISPR-based myostatin-editing efforts in African catfish aquaculture, though translation into applied breeding outcomes will require subsequent functional and expression studies.

Animals↗
PubMed2026

Genome-wide Identification and Expression Profiling Reveal the Galectin Gene Family Diversity and their Possible Role in Antibacterial Mucosal Immunity in Japanese Flounder (Paralichthys olivaceus).

Galectins are a family of proteins that bind specifically to β-galactosides. Their importance in innate immunity of mammals has been well-documented. However, the systematic identification and characterization of galectin gene family remain limited in teleost. In this study, we identified 13 galectin genes (lgals2, lgals2a, lgals2b, lgals3, lgals3a, lgals3b, lgals4, lgals8, lgals8a, lgals9, grp, grp-b, grp-c) from Paralichthys olivaceus genome and analyzed their tissue expressions and expressions in response to Gram-negative and Gram-positive bacterial infections in mucosal tissues (gills, intestine and skin). The P. olivaceus galections were classified into three distinct types based on carbohydrate recognition domains (CRDs). Phylogenetic and syntenic analyses revealed that these galectins are closely related to their counterparts in turbot and zebrafish. Moreover, the transcripts of the 13 galectins were widespread across all tested tissues of healthy fish and regulated following challenge with Vibrio anguillarum or Streptococcus iniae in mucosal tissues, indicating their involvement in P. olivaceus immune response to bacterial infections. The lgals2a was significantly upregulated in the three mucosal tissues by either bacterial infection, whereas lgals9 and grp were basically downregulated in these tissues by either infection. On the other hand, the lgals3b and lgals4 exhibited a bacteria-specific responsive expression as they were upregulated by V. anguillarum whereas remained stable upon S. iniae infection in the gills. We also observed a positive correlation between expression level and bacterial load for the upregulated galectin genes and a negative correlation for the downregulated galectin genes. These results suggest a functional divergence among galectin members in mucosal immunity against bacterial infection in P. olivaceus.

Animals↗