Bridging mouse and human anatomies; a knowledge-based approach to comparative anatomy for disease model phenotyping.

The laboratory mouse is the foremost mammalian model used for studying human diseases and is closely anatomically related to humans. Whilst knowledge about human anatomy has been collected throughout the history of mankind, the first comprehensive study of the mouse anatomy was published less than 60 years ago. This has been followed by the more recent publication of several books and resources on mouse anatomy. Nevertheless, to date, our understanding and knowledge of mouse anatomy is far from being at the same level as that of humans. In addition, the alignment between current mouse and human anatomy nomenclatures is far from being as developed as those existing between other species, such as domestic animals and humans. To close this gap, more in depth mouse anatomical research is needed and it will be necessary to extent and refine the current vocabulary of mouse anatomical terms

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

All in the Name: A Review of Current Standards and the Evolution of Histopathological Nomenclature for Laboratory Animals

The need for international collaboration in rodent pathology has evolved since the 1970s, and was initially driven by the new field of toxicologic pathology. First initiated by the World Health Organization’s International Agency for Research on Cancer for rodents, it has evolved to include pathology of the major species (rats, mice, guinea pigs, nonhuman primates, pigs, dogs, fish, rabbits) used in medical research, safety assessment and mouse pathology. The collaborative effort today is driven by the needs of the regulatory agencies in multiple countries, and by needs of research involving genetically engineered animals, for “basic” research, and for more translational preclinical models of human disease. These efforts led to the establishment of an international rodent pathology nomenclature program. Since that time, multiple collaborations for standardization of laboratory animal pathology nomenclature and diagnostic criteria have been developed, and just a few are described herein. Recently, approaches to a nomenclature that is amenable to sophisticated computation have been made available and implemented for large-scale programs in functional genomics and ageing. Most terminologies continue to evolve as the science of human and veterinary pathology continues to develop, but standardization and successful implementation remain as critical for scientific communication, now as ever in the history of veterinary nosology.Government of Canada through Genome Canada and Ontario Genomics (OGI-051), Commission of the European Community QLRI-1999-CT-0320, the Ellison Medical Foundation, and the National Institutes of Health (CA34196, CA089713, and AG038070-05

Genome-wide screening of mouse knockouts reveals novel genes required for normal integumentary and oculocutaneous structure and function.

Oculocutaneous syndromes are often due to mutations in single genes. In some cases, mouse models for these diseases exist in spontaneously occurring mutations, or in mice resulting from forward mutatagenesis screens. Here we present novel genes that may be causative for oculocutaneous disease in humans, discovered as part of a genome-wide screen of knockout-mice in a targeted single-gene deletion project. The International Mouse Phenotyping Consortium (IMPC) database (data release 10.0) was interrogated for all mouse strains with integument abnormalities, which were then cross-referenced individually to identify knockouts with concomitant ocular abnormalities attributed to the same targeted gene deletion. The search yielded 307 knockout strains from unique genes with integument abnormalities, 226 of which have not been previously associated with oculocutaneous conditions. Of the 307 knockout strains with integument abnormalities, 52 were determined to have ocular changes attributed to the targeted deletion, 35 of which represent novel oculocutaneous genes. Some examples of various integument abnormalities are shown, as well as two examples of knockout strains with oculocutaneous phenotypes. Each of the novel genes provided here are potentially relevant to the pathophysiology of human integumentary, or oculocutaneous conditions, such as albinism, phakomatoses, or other multi-system syndromes. The novel genes reported here may implicate molecular pathways relevant to these human diseases and may contribute to the discovery of novel therapeutic targets

A Review of Current Standards and the Evolution of Histopathology Nomenclature for Laboratory Animals.

The need for international collaboration in rodent pathology has evolved since the 1970s and was initially driven by the new field of toxicologic pathology. First initiated by the World Health Organization's International Agency for Research on Cancer for rodents, it has evolved to include pathology of the major species (rats, mice, guinea pigs, nonhuman primates, pigs, dogs, fish, rabbits) used in medical research, safety assessment, and mouse pathology. The collaborative effort today is driven by the needs of the regulatory agencies in multiple countries, and by needs of research involving genetically engineered animals, for "basic" research and for more translational preclinical models of human disease. These efforts led to the establishment of an international rodent pathology nomenclature program. Since that time, multiple collaborations for standardization of laboratory animal pathology nomenclature and diagnostic criteria have been developed, and just a few are described herein. Recently, approaches to a nomenclature that is amenable to sophisticated computation have been made available and implemented for large-scale programs in functional genomics and aging. Most terminologies continue to evolve as the science of human and veterinary pathology continues to develop, but standardization and successful implementation remain critical for scientific communication now as ever in the history of veterinary nosology

Neto1 Is a Novel CUB-Domain NMDA Receptor–Interacting Protein Required for Synaptic Plasticity and Learning

The N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans

The occurrence of tarsal injuries in male mice of C57BL/6N substrains in multiple international mouse facilities.

Dislocation in hindlimb tarsals are being observed at a low, but persistent frequency in group-housed adult male mice from C57BL/6N substrains. Clinical signs included a sudden onset of mild to severe unilateral or bilateral tarsal abduction, swelling, abnormal hindlimb morphology and lameness. Contraction of digits and gait abnormalities were noted in multiple cases. Radiographical and histological examination revealed caudal dislocation of the calcaneus and partial dislocation of the calcaneoquartal (calcaneus-tarsal bone IV) joint. The detection, frequency, and cause of this pathology in five large mouse production and phenotyping centres (MRC Harwell, UK; The Jackson Laboratory, USA; The Centre for Phenogenomics, Canada; German Mouse Clinic, Germany; Baylor College of Medicine, USA) are discussed