http://vet.sagepub.com/ Veterinary Pathology Online http://vet.sagepub.com/content/49/1/224 The online version of this article can be found at: DOI: 10.1177/0300985811415709 2012 49: 224 originally published online 8 August 2011 Vet Pathol B. Bolon, S. Couto, L. Fiette and K. La Perle Rodents Internet and Print Resources to Facilitate Pathology Analysis When Phenotyping Genetically Engineered Published by: http://www.sagepublications.com On behalf of: Pathologists. American College of Veterinary Pathologists, European College of Veterinary Pathologists, & the Japanese College of Veterinary can be found at: Veterinary Pathology Online Additional services and information for http://vet.sagepub.com/cgi/alerts Email Alerts: http://vet.sagepub.com/subscriptions Subscriptions: http://www.sagepub.com/journalsReprints.nav Reprints: http://www.sagepub.com/journalsPermissions.nav Permissions: What is This? - Aug 8, 2011 OnlineFirst Version of Record - Jan 3, 2012 Version of Record >> by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from by guest on October 11, 2013 vet.sagepub.com Downloaded from
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Internet and Print Resources to Facilitate Pathology Analysis When Phenotyping Genetically Engineered Rodents
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Internet and Print Resources to FacilitatePathology Analysis When PhenotypingGenetically Engineered Rodents
B. Bolon1, S. Couto2, L. Fiette3, and K. La Perle1
AbstractGenetically engineered mice and rats are increasingly used as models for exploring disease progression and mechanisms. The fullspectrum of anatomic, biochemical, and functional changes that develop in novel, genetically engineered mouse and rat lines mustbe cataloged before predictions regarding the significance of the mutation may be extrapolated to diseases in other vertebratespecies, including humans. A growing list of reference materials, including books, journal articles, and websites, has beenproduced in the last 2 decades to assist researchers in phenotyping newly engineered rodent lines. This compilation providesan extensive register of materials related to the pathology component of rodent phenotypic analysis. In this article, theauthors annotate the resources they use most often, to allow for quick determination of their relevance to research projects.
Keywordsfunctional genomics, Internet, mouse, phenogenomics, phenotype, rat, reference, website
In the past 25 years, genetically engineered mice (GEM) and
rats (GER) have advanced from novelty status to essential tools
in biomedical research programs.167,168,220 The driving force
behind this evolution is the conviction that the functional and
structural consequences of altering a rodent gene will be mir-
rored in human patients who carry a similar genetic anomaly
in the homolog gene.204 Supporting the accuracy of this pre-
mise is the fact that the effects in human patients of the 100
top-selling pharmaceutical agents are predicted by the GEM
phenotypes that arise when genes encoding each drug’s target
are deliberately disrupted.245 Another development in genetic
engineering during the last decade has been the generation of
humanized rodent models (ie, substitution of a human molecule
or cell type in place of its native rodent counterpart), thus pro-
viding a system to test the functional and structural significance
of human molecules in vivo.168,243 The push to annotate the
whole mammalian genome by comprehensive gene targeting
in GEM30,130,193 will greatly expand the magnitude of engi-
neered rodent research and its application to human disease
modeling.
Proficient phenotyping of GEM and GER requires regular
access to a range of biomedical expertise. The complexity of
phenotypic analysis typically necessitates a team approach for
greatest success. In many cases, such know-how is provided
within an institution through the assembly of ‘‘comprehensive
centers’’ or ‘‘shared phenotyping resources’’ comprising sev-
eral collaborating research and/or service laboratories. In other
instances, the entire institute is fully dedicated to rodent pheno-
typing. Either strategy is suitable as long as a critical mass of
multidisciplinary expertise is available to support the efforts
of the research team conducting its experiments.
The key bottleneck affecting all rodent phenogenomic pro-
grams, including the international effort to annotate the mam-
malian genome,130 is the inability to perform high-throughput
phenotypic analysis at a pace that matches the generation of
new GEM and GER lines. A chief factor in this phenotyping
backlog is the well-documented dearth of experienced com-
parative pathologists.13,35 This shortage is the outcome of 2 pri-
mary trends in scientific research. First, laboratory animal
pathologists are usually allocated to other research roles, such
as disease diagnosis in laboratory animal facilities or evalua-
tion of rodent tissues from toxicity bioassays. More important,
training programs designed to produce comparative patholo-
gists with substantial experience in rodent-based research are
uncommon, so most individuals who enter the field do so at
present by undertaking an informal course of mentored or
self-directed independent study.24 The major flaw of this indi-
vidualized approach to comparative pathology training is that,
1 The Ohio State University, Columbus, Ohio2 Genentech, Inc., South San Francisco, California3 Institut Pasteur, Paris, France
Corresponding Author:
Dr Brad Bolon, The Ohio State University, Department of Veterinary
Biosciences, 350 Veterinary Medicine Academic Building, 1900 Coffey Road,
Veterinary Pathology49(1) 224-235ª The Author(s) 2012Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/0300985811415709http://vet.sagepub.com
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226
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227
by definition, it fails to provide a standard knowledge base for
individuals engaged in GEM and GER phenotyping projects.
Efforts are currently underway by several organizations (eg,
the Academy of Genomic Pathology, http://ctrgenpath.net/
?page_id¼2612; the ACVP/STP Coalition for Veterinary
Pathology Fellows, http://www.vetpathcoalition.org/) to pro-
duce more consistent training experiences in comparative
pathology emphasizing rodent phenotypic analysis. However,
the curricula and final product (eg, formal degree, continuing
education certificate) have yet to be defined. Therefore, indi-
viduals interested in acquiring knowledge and practical skills
in comparative pathology must continue to pursue their educa-
tion in a self-directed fashion for the present.
A partial remedy for the scarcity of organized training
programs in rodent pathology is to devise a self-study program
based on readily available resources. The current review is
designed to be a multidisciplinary compilation of Internet
and print resources to support a well-rounded autotutorial
Table 2. Essential Internet Resources for Comparative Pathologists Engaged in Phenotypic Analysis of Engineered Rodents
A comprehensive site with text and images that compares placental structure among many species, including rodents. Thesimplest means for accessing mouse and rat data is to use the ‘‘Index’’ button and then scroll to the bottom to find the‘‘Rodentia’’ section.
‘‘Inbred Strains of Mice,’’ http://www.informatics.jax.org/external/festing/mouse/STRAINS.shtml 67This venue provides an alphabetical listing of major mouse strains with links to extensive documentation regardingbiological characteristics. This site offers a thorough overview of strain-specific anatomy and physiology.
‘‘Mouse Brain Library,’’ http://mbl.org/ 241This site catalogs high-resolution images and databases of brains from several mouse strains. Atlases are available withsections in 2 orientations (coronal and horizontal) for various ages.
‘‘Mouse Genome Informatics,’’ http://www.informatics.jax.org 106This portal contains genomic and phenotypic data for many mouse strains. Links provide ready access to searchabledatabases that match mutations (engineered and spontaneous) to phenotypes, describe gene maps and markers, and allowcomparison of genomic information among species.
‘‘Mouse Nomenclature,’’ http://www.informatics.jax.org/mgihome/nomen/index.shtml 107This portal provides entry to rules and guidelines for naming genes, alleles, mutations, chromosomal aberrations, andmouse and rat strains.
‘‘Pathology of Genetically Engineered Mice,’’ http://www.niaid.nih.gov/labsandresources/labs/aboutlabs/cmb/infectiousdiseasepathogenesissection/vetpathology/geneticallyengineeredmice/Pages/geneticallyEngineeredMice.aspx
166
This clearinghouse provides links to numerous sites of relevance to mouse pathologists, including a link to a companionsite dealing with rodent immunohistochemistry.
Pathology nomenclatureThese collections provide a comprehensive list of lesion names and descriptions for common abnormalities in major organsof mice and rats. The older Standardized System of Nomenclature and Diagnostic Criteria guides are currently beingreplaced by the INHAND documents.‘‘Standardized System of Nomenclature and Diagnostic Criteria (SSNDC) Guides,’’ http://www.toxpath.org/ssndc.asp 211‘‘International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice,’’ http://www.toxpath.org/inhand.asp
104
Phenome databasesTaken together, these portals offer a comprehensive compilation of mouse physiologic data that can be searched by strain,organ system, or biological parameter. Links to protocols for acquiring such data are also given.‘‘Europhenome,’’ http://www.europhenome.org/databrowser/viewer.jsp 64‘‘Mouse Phenome Database,’’ http://phenome.jax.org/ 108‘‘Pathbase,’’ http://www.pathbase.net/ 6‘‘Phenotyping of Genetically Engineered Mice,’’ http://dels-old.nas.edu/ilar_n/ilarjournal/47_2/html/ 157
The site provides access to the free online archive of an ILAR Journal issue discussing methods and policy considerations tocontemplate when generating and analyzing mouse colonies with genetically engineered phenotypes.
‘‘Revised Guides for Organ Sampling and Trimming in Rats and Mice,’’ http://reni.item.fraunhofer.de/reni/trimming/index.php 158This site gives access to guides for organ sampling and trimming in mice and rats.
‘‘Visible Mouse Project,’’ http://tvmouse.compmed.ucdavis.edu/ 81The site is a clearinghouse for multimedia presentations describing the anatomy, physiology, histology, and pathology ofthe laboratory mouse, emphasizing the features of genetically engineered mice.
This portal affords entry to information regarding many aspects of rat biology, including links to genomic, proteomic(pathway), functional, phenotypic, and strain data.
228 Veterinary Pathology 49(1)
curriculum in GEM and GER pathobiology and phenotyping.
The cited resources are arranged in 3 tables for convenience.
The first 2 tables reflect the printed materials (eg, books and
journal articles; Table 1) and websites (Table 2) that we most
commonly use in our daily course of comparative pathology
research. Each frequently utilized reference is followed by a
brief description of its content and main features. We recom-
mend that the annotated print items in Table 1 be available in
each pathologist’s departmental library, and ideally in his or
her office. The third table lists topics related to rodent pheno-
typing that occasionally require input from a comparative
pathologist but fall outside the core pathology expertise
expected of such individuals. These latter materials are accom-
panied by a list of one or more nonannotated citations that offer
further discussion on such auxiliary subjects. For some topics
in Table 3 (eg, neuroanatomy atlases for adult mice), multiple
editions of a given book have been produced by the same
authors. All editions have been included in the citation list in
cases where we have found that the various versions may illu-
minate distinct features of the given rodent system.
A solid understanding of the foundational knowledge
required for proficient GEM and GER phenotyping may be
readily attained by a sincere study of the resources in the anno-
tated lists. Sufficient time will have to be spent perusing these
baseline resources so that the budding comparative pathologist
becomes familiar with not only individual facts but also the
location of essential topics of relevance to phenotyping GEM
and GER models. Pathologists who regularly participate in
rodent phenotyping will also need to engage in a lifelong quest
for continuing education due to the rapid evolution of informa-
tion, skills, tools, and techniques within this field.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
References
1. Allen Institute for Brain Science. Brain Atlas Portal. Seattle, WA:
Allen Institute for Brain Science. http://www.brain-map.org/.
Published 2009. Accessed September 21, 2009.
2. Altman J, Bayer SA. Atlas of Prenatal Rat Brain Development.