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1.  Spontaneous asj-2J Mutant Mouse as a Model for Generalized Arterial Calcification of Infancy: A Large Deletion/Insertion Mutation in the Enpp1 Gene 
PLoS ONE  2014;9(12):e113542.
Generalized arterial calcification of infancy (GACI), an autosomal recessive disorder caused by mutations in the ENPP1 gene, manifests with extensive mineralization of the cardiovascular system. The affected individuals in most cases die within the first year of life, and there is currently no effective treatment for this disorder. In this study, we characterized a spontaneous mutant mouse, asj-2J, as a model for GACI. These mice were identified as part of a phenotypic deviant search in a large-scale production colony of BALB/cJ mice at The Jackson Laboratory. They demonstrated a characteristic gait due to stiffening of the joints, with phenotypic similarity to a previously characterized asj (“ages with stiffened joints”) mouse, caused by a missense mutation in the Enpp1 gene. Complementation testing indicated that asj-2J and asj were allelic. PCR-based mutation detection strategy revealed in asj-2J mice a large, 40,035 bp, deletion spanning from intron 1 to the 3′-untranslated region of the Enpp1 gene, coupled with a 74 bp insertion. This was accompanied with a significant reduction in the plasma PPi concentration and reduced PPi/Pi ratio. As a consequence, extensive aberrant mineralization affecting the arterial vasculature, a number of internal organs, and the dermal sheath of vibrissae, a progressive biomarker of the ectopic mineralization process, was demonstrated by a combination of micro computed tomography, histopathology with calcium-specific stains, and direct chemical assay of calcium. Comparison of the asj and asj-2J mice demonstrated that the latter ones, particularly when placed on an acceleration diet high in phosphate and low in magnesium, had more extensive mineralization. Thus, the asj-2J mouse serves as a novel model for GACI, a currently intractable disorder.
doi:10.1371/journal.pone.0113542
PMCID: PMC4257536  PMID: 25479107
2.  Immune Status, Strain Background, and Anatomic Site of Inoculation Affect Mouse Papillomavirus (MmuPV1) Induction of Exophytic Papillomas or Endophytic Trichoblastomas 
PLoS ONE  2014;9(12):e113582.
Papillomaviruses (PVs) induce papillomas, premalignant lesions, and carcinomas in a wide variety of species. PVs are classified first based on their host and tissue tropism and then their genomic diversities. A laboratory mouse papillomavirus, MmuPV1 (formerly MusPV), was horizontally transmitted within an inbred colony of NMRI-Foxn1nu/Foxn1nu (nude; T cell deficient) mice of an unknown period of time. A ground-up, filtered papilloma inoculum was not capable of infecting C57BL/6J wild-type mice; however, immunocompetent, alopecic, S/RV/Cri-ba/ba (bare) mice developed small papillomas at injection sites that regressed. NMRI-Foxn1nu and B6.Cg-Foxn1nu, but not NU/J-Foxn1nu, mice were susceptible to MmuPV1 infection. B6 congenic strains, but not other congenic strains carrying the same allelic mutations, lacking B- and T-cells, but not B-cells alone, were susceptible to infection, indicating that mouse strain and T-cell deficiency are critical to tumor formation. Lesions initially observed were exophytic papillomas around the muzzle, exophytic papillomas on the tail, and condylomas of the vaginal lining which could be induced by separate scarification or simultaneous scarification of MmuPV1 at all four sites. On the dorsal skin, locally invasive, poorly differentiated tumors developed with features similar to human trichoblastomas. Transcriptome analysis revealed significant differences between the normal skin in these anatomic sites and in papillomas versus trichoblastomas. The primarily dysregulated genes involved molecular pathways associated with cancer, cellular development, cellular growth and proliferation, cell morphology, and connective tissue development and function. Although trichoepitheliomas are benign, aggressive tumors, few of the genes commonly associated with basal cell carcinoma or squamous cells carcinoma were highly dysregulated.
doi:10.1371/journal.pone.0113582
PMCID: PMC4256377  PMID: 25474466
3.  Genetic modulation of nephrocalcinosis in mouse models of ectopic mineralization: The Abcc6tm1Jfk and Enpp1asj mutant mice 
Ectopic mineralization of renal tissues in nephrocalcinosis is a complex, multifactorial process. The purpose of this study was to examine the role of genetic modulation and the role of diet in nephrocalcinosis using two established mouse models of ectopic mineralization, Abcc6tm1Jfk and Enpp1asj mice, which serve as models for pseudoxanthoma elasticum and generalized arterial calcification of infancy, two heritable disorders, respectively. These mutant mice, when on standard rodent diet, develop nephrocalcinosis only at very late age. In contrast, when placed on an “acceleration diet” composed of increased phosphate and reduced magnesium content they showed extensive mineralization of the kidneys affecting primarily medullary tubules as well as arcuate and renal arteries, as examined by histopathology and quantitated by chemical assay for calcium. Mineralization could also be detected noninvasively by micro computed tomography. While the heterozygous mice did not develop nephrocalcinosis, compound heterozygous mice carrying both mutant alleles, Abcc6 tm1Jfk/+, Enpp1+/asj, developed ectopic mineralization similar to that noted in homozygous mice for either gene, indicating that deletion of one Abcc6 allele along with Enpp1 haploinsufficiency resulted in renal mineralization. Thus, synergistic genetic defects in the complex mineralization/anti-mineralization network can profoundly modulate the degree of ectopic mineralization in nephrocalcinosis.
doi:10.1038/labinvest.2014.52
PMCID: PMC4039617  PMID: 24732453
Genetic modulation of nephrocalcinosis; mineral content of nephrocalcinosis; mouse models of ectopic mineralization; the role of experimental diet in kidney mineralization
4.  Identification of Genes Important for Cutaneous Function Revealed by a Large Scale Reverse Genetic Screen in the Mouse 
PLoS Genetics  2014;10(10):e1004705.
The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP). A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1), while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1). The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation.
Author Summary
Recent developments in high throughput applications to manipulate and inactivate specific genes in mouse embryonic stem cells (ES cells) have allowed for the initiation of large scale reverse genetic screens in the mouse. The immediate connection of a phenotype to a mutated (null) gene represents a paradigm shift in our ability to explore gene function. This study utilized such a screening approach to investigate the genetic contribution to skin development and homeostasis. Not only does this approach provide insight into the genetics of skin biology, it is also instrumental in generating novel models with which to study the genetic underpinnings of skin disease. Initial screening of 562 mutated genes in mice uncovered previously unrecognized genes involved in the biology of this organ and identified novel functions for previously studied genes associated with epidermal phenotypes. Taken together, these results highlight high throughput screening approaches that are valuable in reverse genetic screening and provide a pool of mouse mutants, available to the scientific community, that will serve as the basis for further detailed investigations into skin function and skin disease.
doi:10.1371/journal.pgen.1004705
PMCID: PMC4207618  PMID: 25340873
5.  Mouse Alopecia Areata and Heart Disease: Know Your Mouse! 
The Journal of investigative dermatology  2013;134(1):10.1038/jid.2013.273.
doi:10.1038/jid.2013.273
PMCID: PMC3825791  PMID: 23774530
Dystrophic cardiac calcinosis; epicardial mineralization and fibrosis; alopecia areata
6.  Lack of response to laser comb in spontaneous and graft induced alopecia areata in C3H/HeJ mice 
The Journal of investigative dermatology  2013;134(1):10.1038/jid.2013.252.
doi:10.1038/jid.2013.252
PMCID: PMC3825825  PMID: 23752043
spontaneous alopecia areata; skin graft-induced alopecia areata; laser comb treatment; autoimmune disease
7.  Alopecia areata: updates from the mouse perspective 
Alopecia areata (AA) is a cell mediated autoimmune disease that targets actively growing hair follicles in mammals, including humans and mice. Development of the C3H/HeJ spontaneous mouse model AA nearly 20 years ago provided a much needed tool to test hypotheses and ultimately serve as a preclinical model for drug testing. Discoveries in both human AA patients and the mouse model supported each other and lead to discoveries on the incredibly complex genetic basis of this disease. The discovery that A/J, MRL/MpJ, SJL/J, and SWR/J strains also develop AA now allows genome wide association mapping studies to expand the list of genes underlying this disease. Potential new targets for unraveling the pathogenesis of AA include the role of retinoic acid metabolism in the severity of disease and hair shaft proteins that may be either the inciting antigen or ultimate target of the immune reaction leading to breakage of the shaft causing clinical alopecia. Comparing these model systems with human and mouse clinical disease, for both discovery and validation of the discoveries, continues to resolve the complex questions surrounding AA.
doi:10.1038/jidsymp.2013.6
PMCID: PMC4071566  PMID: 24326543
vitamin A; C3H/HeJ mice; genetics; mouse models
9.  Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement 
Inflammatory bowel diseases  2013;19(9):1983-1989.
Background
In contrast to the prominent function of the blood vasculature in promoting tissue inflammation, the role of lymphatic vessels in inflammation has been scarcely studied in vivo. To investigate whether modulating lymphatic vessel function might affect the course of chronic inflammation the major lymphangiogenic receptor vascular growth factor receptor 3 (VEGFR-3, FLT4) was blocked in an established model of inflammatory bowel disease.
Methods
Interleukin 10 (IL10)-deficient mice that spontaneously develop inflammatory bowel disease, were treated with a blocking antibody to VEGFR-3 for 2 weeks, and the inflammatory changes in colon tissue, as well as the blood and lymphatic vascularization were quantitatively analyzed.
Results
We found a significant increase in the severity of colon inflammation in anti-VEGFR-3 treated mice. This was accompanied by an increased number of enlarged and tortuous lymphatic vessels, and edema in colon submucosa, indicating impaired lymphatic function. In contrast, no major effects of the treatment on the blood vasculature were observed.
Conclusions
These results indicate that therapies aimed at promoting lymphatic function, e.g., with pro-lymphangiogenic factors such as VEGF-C, might provide a novel strategy for the treatment of inflammatory conditions such as inflammatory bowel disease.
doi:10.1097/MIB.0b013e31829292f7
PMCID: PMC3732464  PMID: 23835443
Lymphangiogenesis; VEGFR-3; colitis
10.  Comparative Anatomy of Mouse and Human Nail Units 
Recent studies of mice with hair defects have resulted in major contributions to the understanding of hair disorders. To use mouse models as a tool to study nail diseases, a basic understanding of the similarities and differences between the human and mouse nail unit is required. In this study we compare the human and mouse nail unit at the macroscopic and microscopic level and use immunohistochemistry to determine the keratin expression patterns in the mouse nail unit. Both species have a proximal nail fold, cuticle, nail matrix, nail bed, nail plate, and hyponychium. Distinguishing features are the shape of the nail and the presence of an extended hyponychium in the mouse. Expression patterns of most keratins are similar. These findings indicate that the mouse nail unit shares major characteristics with the human nail unit and overall represents a very similar structure, useful for the investigation of nail diseases and nail biology.
doi:10.1002/ar.22660
PMCID: PMC3579226  PMID: 23408541
animal model; microscopic; claw; nail
11.  R164C mutation in FOXQ1 H3 domain affects formation of the hair medulla 
Experimental dermatology  2013;22(3):234-236.
A number of single gene mutations in laboratory mice produce hair follicle defects resulting in deformed hair shafts. The radiation induced (SB/LeJ-Foxq1sa) satin mutant mice have a satin-like sheen to their hair and dilute coloration. This sheen is due to failure of the hair shafts to develop normal medullas, while the pigment dilution is due to the unrelated beige (lysosomal trafficking regulator, Lystbg) mutation. A new allelic mutation, Foxq1sa-J, arose spontaneously on the albino (tyrosinase, Tyrc) MRL/MpJ-Faslpr background. The Foxq1sa-J allele has a C to T transition at position 490. By contrast, the Foxq1sa mutant allele was confirmed to be a 67 base pair deletion followed by two base changes (GA to AT). Morphologic changes were similar to those seen in Hoxc13 transgenic and targeted mutant mice. This new allelic mutation provides yet another tool to investigate formation of the interior structures of hair shafts.
doi:10.1111/exd.12106
PMCID: PMC3602905  PMID: 23489430
Foxq1; satin; hair fiber; medulla; gene networks; mouse model
12.  Transplantable malignant melanoma in LT.B6 congenic mice resembling pigmented epithelioid melanocytoma in humans 
Genetically engineered mouse models have been generated to recapitulate major signaling pathways deregulated in melanoma. Although these models are invaluable to delineate the relationship between gene mutations and targeted therapeutics, no spontaneously occurring melanomas are available in laboratory mice, which might be used to discover novel disrupted pathways, other than the widely studied MAPK, PI3-AKT and CDK4-INK4A-RB1. We report multiple spontaneously occurring melanomas on the tail of LT.B6 congenic strain, commonly used to study spontaneous ovarian teratomas. We present the evidence of spontaneous mouse melanoma and successful transplantation into 2 out of 2 mice, thereby enabling a complete histopathologic and clinical characterization. The histopathology of LT.B6 melanomas remarkably resembled a human melanoma subtype, pigmented epithelioid melanocytoma (PEM); and their clinical behavior was similar in indolent growth, metastasis to local lymph nodes and lack of liver metastasis. Lung metastasis was unique in the mice. Using qRT-PCR, we detected the expression of two melanocyte specific genes, Tyrp1 and Mitf, in the transplanted primary tumors and nodal metastases but not liver, confirming the histopathology. This mouse model closely resembled a low-grade variant of human melanoma and could provide the opportunity to globally investigate the genetic and epigenetic alterations associated with metastasis.
doi:10.1038/jid.2014.47
PMCID: PMC4085667  PMID: 24476622
cutaneous melanoma; pigmented epithelioid melanocytoma; mouse model; lymph node; lung; liver; melanoma metastases; tyrosine-related protein 1 and microphthalmia-associated transcription factor
13.  Where’s the mouse info? 
Veterinary pathology  2009;46(6):1241-1244.
doi:10.1354/vp.09-VP-0042-S-COM
PMCID: PMC3804057  PMID: 19605899
databases; genetically engineered mice; phenotyping; record keeping; mouse pathology; mouse pathology informatics
14.  A mouse by any other name… 
doi:10.1038/jid.2009.81
PMCID: PMC3804061  PMID: 19521404
16.  What color is the skin of a mouse? 
Veterinary pathology  2011;49(1):142-145.
doi:10.1177/0300985811417244
PMCID: PMC3756488  PMID: 22096019
17.  Mouse Models for Pseudoxanthoma Elasticum: Genetic and Dietary Modulation of the Ectopic Mineralization Phenotypes 
PLoS ONE  2014;9(2):e89268.
Pseudoxanthoma elasticum (PXE), a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene. Null mice (Abcc6−/−) recapitulate the genetic, histopathologic and ultrastructural features of PXE, and they demonstrate early and progressive mineralization of vibrissae dermal sheath, which serves as a biomarker of the overall mineralization process. Recently, as part of a mouse aging study at The Jackson Laboratory, 31 inbred mouse strains were necropsied, and two of them, KK/HlJ and 129S1/SvImJ, were noted to have vibrissae dermal mineralization similar to Abcc6−/− mice. These two strains were shown to harbor a single nucleotide polymorphism (rs32756904) in the Abcc6 gene, which resulted in out-of-frame splicing and marked reduction in ABCC6 protein expression in the liver of these mice. The same polymorphism is present in two additional mouse strains, DBA/2J and C3H/HeJ, with similar reduction in Abcc6 protein levels, yet these mice did not demonstrate tissue mineralization when kept on standard rodent diet. However, all four mouse strains, when placed on experimental diet enriched in phosphate and low in magnesium, developed extensive ectopic mineralization. These results indicate that the genetic background of mice and the mineral composition of their diet can profoundly modulate the ectopic mineralization process predicated on mutations in the Abcc6 gene. These mice provide novel model systems to study the pathomechanisms and the reasons for strain background on phenotypic variability of PXE.
doi:10.1371/journal.pone.0089268
PMCID: PMC3929712  PMID: 24586646
18.  Molecular Identification of Collagen 17a1 as a Major Genetic Modifier of Laminin Gamma 2 Mutation-Induced Junctional Epidermolysis Bullosa in Mice 
PLoS Genetics  2014;10(2):e1004068.
Epidermolysis Bullosa (EB) encompasses a spectrum of mechanobullous disorders caused by rare mutations that result in structural weakening of the skin and mucous membranes. While gene mutated and types of mutations present are broadly predictive of the range of disease to be expected, a remarkable amount of phenotypic variability remains unaccounted for in all but the most deleterious cases. This unexplained variance raises the possibility of genetic modifier effects. We tested this hypothesis using a mouse model that recapitulates a non-Herlitz form of junctional EB (JEB) owing to the hypomorphic jeb allele of laminin gamma 2 (Lamc2). By varying normally asymptomatic background genetics, we document the potent impact of genetic modifiers on the strength of dermal-epidermal adhesion and on the clinical severity of JEB in the context of the Lamc2jeb mutation. Through an unbiased genetic approach involving a combination of QTL mapping and positional cloning, we demonstrate that Col17a1 is a strong genetic modifier of the non-Herlitz JEB that develops in Lamc2jeb mice. This modifier is defined by variations in 1–3 neighboring amino acids in the non-collagenous 4 domain of the collagen XVII protein. These allelic variants alter the strength of dermal-epidermal adhesion in the context of the Lamc2jeb mutation and, consequentially, broadly impact the clinical severity of JEB. Overall the results provide an explanation for how normally innocuous allelic variants can act epistatically with a disease causing mutation to impact the severity of a rare, heritable mechanobullous disorder.
Author Summary
Epidermolysis bullosa (EB) is a group of rare genetic Mendelian disorders that result in mechanical fragility of the skin and mucosal membranes. Junctional EB is a subset caused by mutations that result in cleavage of the dermal-epidermal junction. All forms of EB demonstrate substantial variability in their clinical phenotype that is not readily explained. The possibility of genetic modifiers as the cause of this variability has been difficult to address in humans. We apply a mouse model carrying a hypomorphic allele of the laminin gamma 2 (Lamc2) gene to address the possibility of genetic modifiers of JEB. We document the potent impact of differing genetic backgrounds on multiple facets of the JEB syndrome expressed in these mice and show that three neighboring amino acid changes within the non-collagenous domain 4 of the collagen XVII protein strongly modify their disease. The study provides a molecular explanation of how a primary mutation that weakens one component of the cutaneous basement membrane is influenced by normally innocuous allelic variants of another component to affect strength of dermal-epidermal adhesion and consequently, the severity of JEB. This approach may guide the genetic prognosis and diagnosis of human EB disorders.
doi:10.1371/journal.pgen.1004068
PMCID: PMC3923665  PMID: 24550734
19.  Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling 
PLoS ONE  2014;9(1):e85666.
SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1−/− mice, which lack mature B and T cells, were crossed with Sharpin−/− mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra−/− mice, unresponsive to both IL4 and IL13, were crossed with Sharpin−/− mice. Double homozygous Sharpin−/−, Il4ra−/− mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin−/−, Il4ra−/− double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin−/−, Il4ra−/− mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin−/− mice and this was maintained in Sharpin−/−, Il4ra−/− mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling indicating that these cytokines normally play an anti-inflammatory role in SHARPIN-deficient mice.
doi:10.1371/journal.pone.0085666
PMCID: PMC3897490  PMID: 24465642
20.  SHARPIN Regulates Uropod Detachment in Migrating Lymphocytes 
Cell reports  2013;5(3):10.1016/j.celrep.2013.10.011.
SUMMARY
Sharpin-deficient mice display a multiorgan chronic inflammatory phenotype suggestive of altered leukocyte migration. We therefore studied the role of SHARPIN in lymphocyte adhesion, polarization and migration. We found that SHARPIN localizes to the trailing edges (uropods) of both mouse and human chemokine-activated lymphocytes migrating on ICAM-1, which is one of the major endothelial ligands for migrating leukocytes. SHARPIN-deficient cells adhere better to ICAM-1 and show highly elongated tails when migrating. The increased tail lifetime in SHARPIN-deficient lymphocytes decreases the migration velocity. The adhesion, migration and uropod defects in SHARPIN deficient lymphocytes were rescued by reintroducing SHARPIN into the cells. Mechanistically we show that SHARPIN interacts directly with LFA-1, a leukocyte counter-receptor for ICAM-1, and inhibits the expression of intermediate and high-affinity forms of LFA-1. Thus SHARPIN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells.
doi:10.1016/j.celrep.2013.10.011
PMCID: PMC3852511  PMID: 24210817
22.  One medicine, one pathology, and the one health concept 
Journal of the American Veterinary Medical Association  2009;234(12):10.2460/javma.234.12.1530.
doi:10.2460/javma.234.12.1530
PMCID: PMC3804058  PMID: 19527123
23.  SHARPIN is a key regulator of immune and inflammatory responses 
Mice with spontaneous mutations in the Sharpin gene develop chronic proliferative dermatitis that is characterized by eosinophilic inflammation of the skin and other organs with increased expression of type 2 cytokines and dysregulated development of lymphoid tissues. The mutant mice share phenotypic features with human hypereosinophilic syndromes. The biological function of SHARPIN and how its absence leads to such a complex inflammatory phenotype in mice are poorly understood. However, recent studies identified SHARPIN as a novel modulator of immune and inflammatory responses. The emerging mechanistic model suggests that SHARPIN functions as an important adaptor component of the linear ubiquitin chain assembly complex that modulates activation of NF-κB signaling pathway, thereby regulating cell survival and apoptosis, cytokine production and development of lymphoid tissues. In this review, we will summarize the current understanding of the ubiquitin-dependent regulatory mechanisms involved in NF-κB signaling, and incorporate the recently obtained molecular insights of SHARPIN into this pathway. Recent studies identified SHARPIN as an inhibitor of β1-integrin activation and signaling, and this may be another mechanism by which SHARPIN regulates inflammation. Furthermore, the disrupted lymphoid organogenesis in SHARPIN-deficient mice suggests that SHARPIN-mediated NF-κB regulation is important for de novo development of lymphoid tissues.
doi:10.1111/j.1582-4934.2012.01574.x
PMCID: PMC3402681  PMID: 22452937
Sharpin; immune system; inflammation; chronic dermatitis; NF-κB; ubiquitination; lymphoid organogenesis; eosinophilic dermatitis; scaly skin disease
24.  The mouse pathology ontology, MPATH; structure and applications 
Background
The capture and use of disease-related anatomic pathology data for both model organism phenotyping and human clinical practice requires a relatively simple nomenclature and coding system that can be integrated into data collection platforms (such as computerized medical record-keeping systems) to enable the pathologist to rapidly screen and accurately record observations. The MPATH ontology was originally constructed in 2,000 by a committee of pathologists for the annotation of rodent histopathology images, but is now widely used for coding and analysis of disease and phenotype data for rodents, humans and zebrafish.
Construction and content
MPATH is divided into two main branches describing pathological processes and structures based on traditional histopathological principles. It does not aim to include definitive diagnoses, which would generally be regarded as disease concepts. It contains 888 core pathology terms in an almost exclusively is_a hierarchy nine layers deep. Currently, 86% of the terms have textual definitions and contain relationships as well as logical axioms to other ontologies such the Gene Ontology.
Application and utility
MPATH was originally devised for the annotation of histopathological images from mice but is now being used much more widely in the recording of diagnostic and phenotypic data from both mice and humans, and in the construction of logical definitions for phenotype and disease ontologies. We discuss the use of MPATH to generate cross-products with qualifiers derived from a subset of the Phenotype and Trait Ontology (PATO) and its application to large-scale high-throughput phenotyping studies. MPATH provides a largely species-agnostic ontology for the descriptions of anatomic pathology, which can be applied to most amniotes and is now finding extensive use in species other than mice. It enables investigators to interrogate large datasets at a variety of depths, use semantic analysis to identify the relations between diseases in different species and integrate pathology data with other data types, such as pharmacogenomics.
doi:10.1186/2041-1480-4-18
PMCID: PMC3851164  PMID: 24033988
Pathology; Ontology; Disease; Mouse; Phenotype
25.  New approaches to the representation and analysis of phenotype knowledge in human diseases and their animal models 
Briefings in Functional Genomics  2011;10(5):258-265.
The systematic investigation of the phenotypes associated with genotypes in model organisms holds the promise of revealing genotype–phenotype relations directly and without additional, intermediate inferences. Large-scale projects are now underway to catalog the complete phenome of a species, notably the mouse. With the increasing amount of phenotype information becoming available, a major challenge that biology faces today is the systematic analysis of this information and the translation of research results across species and into an improved understanding of human disease. The challenge is to integrate and combine phenotype descriptions within a species and to systematically relate them to phenotype descriptions in other species, in order to form a comprehensive understanding of the relations between those phenotypes and the genotypes involved in human disease. We distinguish between two major approaches for comparative phenotype analyses: the first relies on evolutionary relations to bridge the species gap, while the other approach compares phenotypes directly. In particular, the direct comparison of phenotypes relies heavily on the quality and coherence of phenotype and disease databases. We discuss major achievements and future challenges for these databases in light of their potential to contribute to the understanding of the molecular mechanisms underlying human disease. In particular, we discuss how the use of ontologies and automated reasoning can significantly contribute to the analysis of phenotypes and demonstrate their potential for enabling translational research.
doi:10.1093/bfgp/elr031
PMCID: PMC3189694  PMID: 21987712
phenotype; animal model; disease; database; comparative phenomics; ontology

Results 1-25 (79)