The International Mouse Phenotyping Consortium (IMPC; https://www.mousephenotype.org/) web portal contains phenotype data for mouse protein-coding genes derived from analysis of data obtained in a systematic and high-throughput fashion from knock-out lines produced by IMPC. The project has produced >1400 candidate mouse models of human disease that recapitulate phenotypes observed in patients. Over 8000 papers rely on data or reagents generated by IMPC, demonstrating the impact of the project on the research and clinical communities, and IMPC data is incorporated into other resources, such as MGI, Open Targets, and UniProt. Data release (DR23.0, 2025) contains >100 million data points from 9277 genes and identified 113 803 significant phenotypes. To manage efficient access to this quantity of high dimensional data the IMPC web portal has been rebuilt using a cloud native architecture. The modern user interface retains the look and feel of the original portal with improvements identified through a usability study. New data visualization and training materials for large scale data access through the API have also been developed to make the resource easier to use.

The neurodevelopmental disorder Prader-Willi syndrome (PWS) is caused by loss of paternally-derived gene expression from the imprinted interval on chromosome 15q11-q13. Recently, it has been suggested that the abnormal feed-related behaviours characteristic of PWS may be, in part, developmentally programmed in utero via abnormal placental function. Using mouse models, we test whether the PWS-genes are expressed in placenta and whether this expression is altered in a PWS mouse model (PWSdel). We show that most are, and that expression is significantly reduced in the placenta of PWSdel mice. Moreover, expression of two PWS-transcripts, Necdin and the lncRNA Sngh14 , significantly co-localises with endothelial cells in the labyrinth zone (lz) of the placenta. Critically, in the PWSdel mice, this results in a ~25% reduction in Kdr -positive endothelial cells in the lz, although this did not directly translate into a significant reduction in fetal growth. Together these data suggest that placental function and nutrient transfer from mother to fetus may be compromised in PWS, and that the later post-natal phenotype may be partially programmed in utero . ### Competing Interest Statement The authors have declared no competing interest. Foundation for Prader-Willi Research, https://ror.org/05dxwnm86 Engineering and Physical Sciences Research Council, EP/T02593X/1 Nvidia (United Kingdom)

Abstract This book presents the first comprehensive overview of Home Cage Monitoring (HCM) in rodents, examining how these technologies may contribute to addressing some of the key challenges in animal research. HCM systems provide a method for continuous, automated observation of laboratory animals within their home environment, allowing for reduced handling and environmental disruption. This approach supports efforts to improve data quality and reproducibility in behavioural and physiological research and aligns with the principles of Replacement, Reduction, and Refinement (3Rs). To facilitate knowledge exchange and methodological alignment among researchers using HCM systems, the COST TEATIME Action (CA20135) was established. This chapter presents the collective work of TEATIME Working Groups and includes: A definition of HCM, developed through a structured conceptual framework. A literature review covering publications from 1974 to 2024. A catalogue of available HCM systems, both commercial and self-made. An international survey of 279 professionals across research, facility management, animal care, and technology development. Survey and literature findings indicate growing interest in HCM, but also highlight common limitations, including high setup costs, challenges with group housing, and data management workload. Despite this, continued development and standardisation efforts are likely to drive wider adoption and application of HCM technologies in basic and preclinical research.

Abstract The high efficiency of genome editing presents a challenge when modifying genes associated with viability, welfare, or fertility issues, as implementation of the technology frequently results in mosaic animals with bi-allelic mutations. Combining deactivated Cas9 (dCas9) with Cas9 has been proposed as a strategy to protect one of the two target alleles from editing. We piloted this strategy with 11 genes that are reported as homozygous lethal or associated with welfare issues. We showed that the viability of founders was significantly increased when using 80:20 or 90:10 dCas9:Cas9 ratios, whereas the 70:30 ratio did not yield an equivalent protective effect. The associated overall production rate of mutated founder per manipulated embryo was significantly higher for the 80:20 ratio. Concomitantly, an increased proportion of dCas9 was associated with a significant increase in retention of unedited target alleles but, importantly, did not hinder germline transmission. In addition, editing genes in a paralog cluster with a combination of dCas9 and Cas9 reduced unwanted off-target editing, illustrating a further potential applicability of this approach. This study defines the optimal ratio between dCas9 and Cas9 for strategies aimed at achieving mono-allelic mutations within mosaic founders and proposes a means to reduce the incidence of off-target effects in experiments with limited gRNA options.

Eneboparatide, a long-acting modified form of parathyroid hormone, increases serum calcium levels without increasing urine calcium in mice with autosomal dominant hypocalcemia type 1.

COST Action TEATIME unites experts to advance automated monitoring technologies for laboratory animals, with a focus on Home Cage Monitoring (HCM) systems. The use of HCM has great potential to revolutionise welfare monitoring by enabling continuous, non-invasive tracking of physiological and behavioural patterns in group-housed animals within their undisturbed housing environment. These systems capture spontaneous behaviours - such as feeding, grooming, social interactions and sleep cycles - across day and night phases, offering objective data for welfare and scientific assessments. This real-time monitoring might allow for early detection of distress, disease progression and subtle welfare changes, supporting timely interventions and refined humane endpoints. Unlike traditional clinical scoring, which relies on brief daily observations, HCM provides longitudinal, individualised insights and reduces observer bias. It might also facilitate better characterisation of positive affective states, contributing to more holistic welfare evaluations. Despite technological progress, challenges remain in data integration, sensitivity and standardisation across facilities. Effective implementation requires real-time alert capabilities, robust data management, and interdisciplinary collaboration among scientists, veterinarians and data experts. HCM systems should complement - not replace - human expertise, enriching welfare monitoring and scientific reproducibility. Their integration can improve husbandry, refine severity assessments, advancing both animal welfare and scientific replicability.

[This corrects the article DOI: 10.3389/fcvm.2025.1695034.].

Animal use in preclinical research is facing growing scientific, ethical and political scrutiny in Europe. Researchers are increasingly required to justify in vivo studies and are urged to replace them with New Approach Methodologies (NAMs), even where these are not yet fit for purpose. In response to this pressure, members of the COST Action CA20135 “Improving biomedical research by automated behaviour monitoring in the animal home-cage” (TEATIME) held a Strategic Foresight Workshop in March 2025 to examine the future of animal research in Europe. The resulting scenarios reveal risks of over-regulation, outsourcing animal experiments to countries with weaker standards, and erosion of research quality, but also highlight opportunities to combine validated NAMs with high-quality in vivo work under robust ethical oversight. This short communication summarises the workshop's main insights and argues for evidence-based, transparent and internationally aligned regulation that protects both animal welfare and the scientific value of preclinical research.

Purpose:Analyze phenotypic data from knockout mice with late-adult retinal pathologic phenotypes to identify genes associated with development of adult-onset retinal diseases. Methods:The International Mouse Phenotyping Consortium (IMPC) database was queried for genes associated with abnormal retinal phenotypes in the late-adult knockout mouse pipeline (49-80 weeks postnatal age). We identified human orthologs and performed protein-protein analysis and biological pathways analysis with known inherited retinal disease (IRD) and age-related macular degeneration (AMD) genes using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), PLatform for Analysis of single cell Eye in a Disk (PLAE), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Results:Screening of 587 late-adult mouse genes yielded 12 with abnormal retinal phenotypes, which corresponded to 20 human orthologs. Three of the 12 mouse genes and two of the 20 human orthologs were previously implicated in retinal pathology or physiology in a literature review. Although all of the genes demonstrated retinal pathology when deleted from the mouse genome, most do not have established roles in human retinal disease. Furthermore, human protein-protein analysis and biological pathway analysis yielded only a few relationships between the candidate gene list and that of known IRD and AMD genes, suggesting they may represent novel retinal functions. Conclusions:We identified 12 mouse genes with significant late-adult abnormal retinal pathology, eight of which have not been previously implicated in either mouse or human retinal physiology or pathology. These serve as novel retinal disease gene candidates for late-onset retinal disease.

Inconsistent characterization and reporting of laboratory animal genetics undermine research quality and reproducibility. We need to recognize the value of genetic characterization, improve training for researchers, and implement rigorous reporting standards.

Abstract Background Significant progress has been made in elucidating the genetic underpinnings of Autism Spectrum Disorder (ASD). However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals. Methods We used the macaque Genotype and Phenotype (mGAP) resource consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes. Results We demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-associated genes exhibit significant constraint in macaques (p = 9.4 × 10− 27). Among macaques, many key ASD-implicated genes were observed to harbour predicted damaging mutations. A small number of key ASD-implicated genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes associated with intellectual disability (p = 1.1 × 10− 46), epilepsy (p = 2.1 × 10− 33) and schizophrenia (p = 4.2 × 10− 45), and for an overlapping neurodevelopmental gene set (p = 4.0 × 10− 10). Limitations The lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates. Conclusion The presence of pathological mutations in ASD genes among macaques, along with evidence of similar genetic constraints to those in humans, provides a strong rationale for further investigation of genotype-phenotype relationships in macaques. This highlights the importance of developing primate models of ASD to elucidate the neurobiological underpinnings and advance approaches for precision medicine and therapeutic interventions.

IntroductionMouse models play a critical role in cardiology research, offering valuable insights into the molecular mechanisms, genetics, and potential treatments for cardiovascular diseases. However, the ability to transfer findings in mice between studies is limited by the absence of standardized protocols and valid reference values for the assessment of normal cardiac function in mice. This study aims to establish comprehensive transthoracic echocardiography (TTE) reference ranges for mice, particularly focusing on C57BL/6N wild-type controls.MethodsThe study, which includes data from over 15,000 mice through the International Mouse Phenotyping Consortium (IMPC), highlights how variables such as sex, age, body weight, and anesthesia impact TTE parameters.ResultsThe findings showed that anesthesia is the primary predictor of variability in cardiac function. Isoflurane- and tribromoethanol-anesthetized mice presented with modified cardiac function compared with conscious mice. In addition, we observed minimal sex differences in cardiac morphology and function, except for small variations influenced by anesthesia. The effects of aging on cardiac function were modest, characterized by a decrease in heart rate and subtle changes in ventricular dimensions without evidence of pathological remodeling, possibly attributable to disease-free cardiovascular aging.DiscussionValidation of the reference ranges across multiple mouse strains showed that these values provide a reliable baseline for experiments involving cardiac function in mice. The data underscore the importance of using anesthesia-specific reference values when interpreting TTE results, ensuring robust comparisons in genetic and pharmacological studies. These reference ranges serve as quality assurance tools for future cardiac studies in mice, offering insights into typical TTE parameter values, supporting the detection of experimental perturbations, and contributing to more effective translation of findings from mice to humans.

Purpose:This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans. Methods:The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG). Results:Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions with known human CD genes. PANTHER analysis identified six biological processes shared with established human CD genes. Two genes (Rgs2 and Galnt9) were involved in pathways related to human corneal diseases, including cGMP-PKG signaling, mucin-type O-glycan biosynthesis, and oxytocin signaling. Other candidates were implicated in pathways such as pluripotency of stem cells, MAPK signaling, WNT signaling, actin cytoskeleton regulation, and cellular senescence. Conclusions:This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology. These genes may serve as potential therapeutic targets for treating corneal diseases in aging human populations.

Single-view-based anomaly detection approaches present challenges due to the lack of context, particularly for multi-label problems. In this work, we demonstrate the efficacy of using multiview image data for improved classification using a hierarchical learning approach. Using 170,958 images from the International Mouse Phenotyping Consortium (IMPC) repository, a specimen-wise multiview dataset comprising 54,046 specimens was curated. Next, two hierarchical classification frameworks were developed by customizing ConvNeXT and a convolutional autoencoder (CAE) as CNN backbones, respectively. The customized architectures were trained at three hierarchy levels with increasing anatomical granularity, enabling specialized layers to learn progressively more detailed features. At the top level (L1), multiview (MV) classification performed about the same as single views, with a high mean AUC of 0.95. However, using MV images in the hierarchical model greatly improved classification at levels 2 and 3. The model showed consistently higher average AUC scores with MV compared to single views such as dorsoventral or lateral. For example, at Level 2 (L2), the model divided abnormal cases into three subclasses, achieving AUCs of 0.65 for DV, 0.76 for LV, and 0.87 for MV. Then, at Level 3 (L3), it further divided these into ten specific abnormalities, with AUCs of 0.54 for DV, 0.59 for LV, and 0.82 for MV. A similar performance was achieved by the CAE-driven architecture, with mean AUCs of 0.87, 0.88, and 0.89 at Level 2 (L2) and 0.74, 0.78, and 0.81 at Level 3 (L3), respectively, for DV, LV, and MV views. The overall results demonstrate the advantage of multiview image data coupled with hierarchical learning for skeletal abnormality detection in a multi-label context.

The International Mouse Phenotyping Consortium (IMPC; https://www.mousephenotype.org/) web portal contains phenotype data for mouse protein-coding genes derived from analysis of data obtained in a systematic and high-throughput fashion from knock-out lines produced by IMPC. The project has produced >1,400 mouse models of human disease that recapitulate phenotypes observed in patients. Over 8000 papers rely on data or reagents generated by IMPC, demonstrating the impact of the project on the research and clinical communities, and IMPC data is incorporated into other resources, such as MGI, Open Targets and UniProt. Data release (DR23.0, 2025) contains > 100 million data points from 9,277 genes and identified 113,803 significant phenotypes. To manage efficient access to this quantity of high dimensional data the IMPC web portal has been rebuilt using a cloud native architecture. The modern user interface retains the look and feel of the original portal with improvements identified through a usability study. New data visualisation and training materials for large scale data access through the API have also been developed to make the resource easier to use.

Abstract Purpose Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood. The purpose of this study was to analyze phenotype data from 8,707 knockout mouse lines to identify new genes associated with the development of CDs in humans. Methods 8,707 knockout mouse lines phenotyped by the International Mouse Phenotyping Consortium were queried for genes associated with statistically significant (P < 0.0001) abnormal cornea morphology to identify candidate CD genes. Corneal abnormalities were investigated by histopathology. A literature search was used to determine the proportion of candidate genes previously associated with CDs in mice and humans. Phenotypes of human orthologues of mouse candidate genes were compared with known human CD genes to identify protein-protein interactions and molecular pathways using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes. Results Analysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes. Of these, 37 (17%) genes were previously known to be associated with CD, including 14 in the mouse, 16 in humans, and 7 in both. The remaining 176 (83%) genes have not been previously implicated in CD. We also searched publicly available RNAseq data and found that 131 of the total 213 (61.5%) were expressed in adult human corneal tissue. STRING analysis showed several interactions within and between candidate and established CD proteins. All cellular pathways of the established genes were found in the PANTHER analysis of the candidate genes. Several of the candidate genes were implicated in corneal disease, such as TGF-ß signaling. We also identified other possible underappreciated mechanisms relevant to the human cornea. Conclusions We identified 213 mouse genes that resulted in statistically significant abnormal corneal phenotypes in knockout mice, many of which have not previously been implicated in corneal pathology. Bioinformatic analyses implicated candidate genes in several signaling pathways which are potential therapeutic targets.

Gain-of-function mutations of the calcium-sensing receptor (CaSR) result in autosomal dominant hypocalcemia type 1 (ADH1), which may cause symptomatic hypocalcemia with low parathyroid hormone concentrations. Negative allosteric CaSR modulators, known as calcilytics, have potential as a targeted ADH1 therapy and comprise two main classes, which are the amino alcohols and the quinazolinones. Amino alcohol calcilytics have been assessed as ADH1 therapies but may not be effective for all ADH1-causing mutations. We therefore evaluated quinazolinone calcilytics (ATF936 and AXT914) as an alternate ADH1 treatment. Calcilytic docking studies were performed using reported cryo-EM CaSR structures. In vitro dose-response studies were performed using CaSR-expressing HEK293 cells and in vivo studies undertaken in mice with a gain-of-function CaSR mutation, Leu723Gln, known as Nuf. ATF936 and AXT914, as well as the amino alcohol calcilytics, NPS 2143 and NPSP795, were shown to bind at a common region within the CaSR transmembrane domain, which is also an ADH1 mutational hotspot. Treatment of cells expressing the Nuf mutant (Gln723) CaSR with 1 to 20 nM AXT914 caused dose-dependent decreases in CaSR-mediated intracellular calcium responses with 10 nM AXT914 normalizing the gain of function. Oral administration of 10 mg/kg AXT914 to Nuf mice increased parathyroid hormone to 104 ± 29 pmol/l compared with 23 ± 4 pmol/l for vehicle-treated mice, p < 0.05; and increased plasma albumin-adjusted calcium to 2.03 ± 0.02 mmol/l compared with 1.84 ± 0.02 mmol/l for vehicle-treated mice, p < 0.001. These studies indicate that quinazolinone calcilytics may have potential for treating ADH1.