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The Mouse AtlasDatabase: a community

resource for mouse

development

Biologists who study mouse developmentneed to access and analyse large amountsof diverse information relating to genefunction in the embryo. Gene expressionpatterns, mutant phenotypes,experimental results and descriptions ofnormal development all need to beintegrated. The data that developmentalbiologists use in their analyses come inmany different forms (tables, images, text)making them difficult to combine. Toaddress this problem, we are developingthe Mouse Atlas Database as abioinformatics framework for gene-function data at the organism level1. Thispublic resource currently comprises twocomponents: a controlled vocabulary todescribe the developing anatomy and aseries of digital 3D model embryos. Laterthe system will include a database ofgraphical gene-expression data. Buildingthe system is an ongoing project, but, withthe publication on the Internet of thecontrolled anatomical vocabulary, and thefirst model embryos on CD, there is now aresource that biologists can begin to useand comment on.

The Mouse Atlas CD can be used withNetscape 4.5 or Internet Explorer 4.0 (5.0on Macs) (Boxes 1 and 2). The Atlas andother resources are available on theInternet at http://genex.hgu.mrc.ac.uk/,though the CD will work faster.

Controlled vocabulary for anatomy

The anatomical vocabulary2 (withsynonyms) includes all major structuresthat are visible in conventionally stainedhistological sections (i.e. sections fromparaffin-imbedded material stained withhaematoxylin and eosin), but not domainsthat are only delineated by geneexpression. The ~8000 items in thevocabulary cover all 26 Theilerdevelopmental stages3 (E0–E17.5) and areorganized in the form of a hierarcy ofstructures that specify ‘part of ’relationships. This is implemented in aweb-accessible database with thehierarchy displayed as a series of lists, onefor each Theiler stage (Fig. 1, Box 1).

Although the present version of thecontrolled vocabulary list covers all majortissues, researchers will probably want tomake additions to the database or usedifferent hierarchical groups. The authorsare keen to include this expert knowledgeand to make additions and correctionsaccordingly. Indeed, because no singlehierarchical arrangement of parts willsatisfy all requirements, software is beingimplemented that will allow theresearcher to reorganize the same basiccomponents into alternative hierarchiesand groups. The authors welcome specificsuggestions for such alternative views ofthe vocabulary.

3D model embryos

The second component of the Atlas is aseries of digital 3D models of embryos. Theaim is to provide at least one model foreach successive Theiler stage (TS). Atpresent, models for each post-implantation stage up to 9 days ofdevelopment (TS7–14) are available onCD (Box 2). Later stages will be added asthey are completed: models of embryos at9.5 days (TS15), 12.5 days (TS20) and 17.5days (TS26) of development are inprogress (regularly updated draftmaterial will be available at the web sitethrough the online CD-ROM page). Eachmodel shows the stained, histological

structure of the embryo with the majoranatomical parts delineated4,5. Forembryos at 8.5 days of development(TS13) and older, the models will be basedon the original paraffin-embeddedspecimens illustrated in The Atlas ofMouse Development6.For youngerembryos, new plastic-embeddedspecimens have been used to achievehigher resolution. Each model embryocomprises an array of picture elements(voxels) whose dimensions define thespatial resolution; 2 × 2 × 2 µm for earlystages (fertilization to 8 days TS1–12) and~4 × 4 × 7 µm for later stages. As acommunity resource, the CD is availableto academic sites at nominal cost (seewebsite). Because the Atlas aims to be anauthoritative description of normal mousedevelopment, feedback will be welcomedand anyone with expertise in a particularaspect of development who would like tocontribute to the continuing process ofannotating the models is encouraged tocontact the authors.

Using the Mouse Atlas

The Atlas can be used as a laboratorybench tool. Together with the supportingstaging guide, the digital models andcontrolled vocabulary can be used to helpdetermine developmental stage andidentify anatomical structures. The

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Software Review

The top-level page provides a descriptionof the controlled vocabulary. This isavailable in XML, including uniqueidentifiers for use as keywords, cross-referencing and linking. The data is alsoaccessible through CORBA, whichprovides a powerful program interface.The primary links from this page are: • Staging criteria:a detailed description

of how the Theiler stages are defined andhow we have extended the system toinclude other timing measures. Therelationships between the systems aredefined.

• Anatomy database: a controlledvocabulary for each stage. This isavailable as a text table that provideslinks to diagrams and text describingthe stage. The controlled vocabularycan also be viewed using a Javabrowser, which displays an interactive

tree of the nomenclature with optionsfor search and further detail. Theviewers can be used to obtain both thename and the accession number foreach component for precise cross-referencing.

• Search: enter a text sub-string oraccession number to get details ofmatching components in the anatomydatabase.

• Notes: more detail on how thevocabulary was developed and thegeneral principles of naming andgrouping of terms.

The minimum requirement for viewingthe database is a World-Wide Webbrowser. The Java interfaces require abrowser that can include the Java 2 plug-in [available for MS Windows and Unixplatforms now, Mac OS in due course(see http://www.apple.com/java/)]

Box 1.The Anatomy Database (http://genex.hgu.mrc.ac.uk/Databases/Anatomy)

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models can also be used to interpret one’sresults by exploring the 3D relationshipbetween parts of the embryo and byfollowing their development from onestage to the next. For this, two softwaretools are available on the CD; these allow

the same models to be viewed either aswhole embryos or as a series of histologicalsections. SectionBrowser provides aselection of pre-calculated section planes(Fig. 1), and EmbryoView allows the wholeembryo to be visualized as if it were lying

in a dish illuminated from below (Fig. 2).Other basic features allow the user to panthrough all sections in the three cardinalplanes (although without anatomicalannotation) and to view the originalimages of the transverse sections fromwhich the models were built. Theseprovide a higher-resolution view of thehistology in each part of the embryo.These facilities are introduced in a simplehelp page for first-time users.

The facility to view the histologicalstructure of a stained specimen in a varietyof different ways with the aid of high-resolution anatomical annotation providesa powerful new tool for developmentalbiologists. Suppose, for example, onewishes to identify tissues labelled by areporter gene in a whole-mountpreparation. By choosing the appropriate-stage model in EmbryoView, interactive3D views of the reference embryo thathighlight landmark structures can beselected. These views can then be used tohelp determine which structures might belabelled in the specimen. For histologicalmaterial SectionBrowser can be used tochoose the cutting plane that correspondsto the relevant sections. As the cursor ismoved over the section, structures andtissues are highlighted with their namesdisplayed above the image. Clicking on astructure causes its position in theanatomical hierarchy to be highlighted.These features help identification oflabelled expression domains, structuresaffected in mutants, and so on. In thiscontext, the Atlas will also be useful ininterpreting information from otherdatabases. The obvious example is theGXD, the textual database that linksmouse gene expression data todevelopmental anatomy7. As the MouseAtlas and the GXD use the sameanatomical nomenclature, movement fromone to the other is straightforward. Thus,for example, the Atlas can be used toexplore the spatial and developmentalrelationships between named tissues thatexpress different genes as recorded in theGXD.

The Atlas will also be useful in writingpapers, and we encourage developmentalbiologists to use the anatomicalnomenclature to describe their results, inparticular in tables, abstracts or askeywords. By doing so, researchers willautomatically provide search terms forfuture database queries, and to facilitatethis the Atlas database provides each

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The CD is available to non-profit researchlabs at minimal cost (select ‘Order a CD’).

Browsing the CD on PCs, Macs orUNIX workstations requires a Java-enabled www browser such asNetscape 4.5 or Internet Explorer 4.0 (5.0on Macs). These include, by default, therequired version of Java (1.1.5). A simplehelp page is available for first-timeusers.

To use the advanced software,SectionView and MAPaint, a UNIXmachine with X11 is necessary. Theprogram will run on Sun Workstations(Solaris 2.6), Silicon Graphics Workstations(IRIX 5 or IRIX6) or PC compatibles (RedHatLinux 6.2 or Solaris 8)

A test page is available on the CD tohelp users see what can be run on theirparticular set-up.

Box 2.The CD-ROM (http://genex.hgu.mrc.ac.uk/CDROM_Copyrights/)

Fig. 1. The anatomy SectionBrowser allows the user to select digital sections through each embryo (Theiler Stages7–14). This resource is designed to help the researcher explore the histological structure of the embryo and identifyanatomical parts. For this a view is selected (lower left) and the red line is dragged to the desired position. The sectionis displayed in the left window and the anatomy database on the right. By moving the mouse cursor across thesection, anatomical structures can be highlighted with their names appearing at the bottom of the window. Clickingon the section highlights the name of the corresponding structure in the database and vice versa. Structures thathave been delineated in the model embryos and that appear in the current section are indicated by an asterisk in thedatabase display. A simple list of these structures can be displayed by clicking on the ‘select component’ box at thetop of the section window and individual structures selected for highlighting. Instructions are on the same page,below the part shown here.

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anatomical component with both astandard name and a unique identifier.

An additional role for the Atlasdatabase will be to help integrateinformation from future studies of genefunction. In particular, new databasesrelating to gene function in the embryo –for example, gene-expression results frommicroarrays and databases of mutantphenotypes – could use the standardanatomical vocabulary and modelembryos to annotate results. The authorswelcome suggestions for adaptations tothe Atlas data that might be needed forthese applications.

Scientists who want to use the CD as amore sophisticated research aid can usetwo advanced tools that run in a variety ofUNIX environments (Box 2) and that canload and manipulate an entire modelembryo. SectionView allows the user to cutsections interactively in any plane, for

example to find the best match ofhistological material from a particularexperiment. The program allows the majoranatomical structures to be highlighted indifferent colours in these sections andenables simultaneous exploration ofseveral sections through the same model.MAPaint allows researchers to paint gene-expression patterns or other spatialdomains directly into the model embryo,section by section, and to save these 3Ddomains as files that can be reloaded lateror shared between labs. These programscan also be downloaded from the genexweb page (http://genex.hgu.mrc.ac.uk/),but the model embryos are very large, andare therefore available only on the CD.Additional UNIX software is beingdeveloped that will allow data to bemapped into the Atlas models directly fromimages of experimental results. Apreliminary version of this software can beobtained from the authors.

Future applications

The Atlas is designed to provide thebioinformatics framework for communitydatabases of mouse development. Tofacilitate this, we are building a graphicaldatabase that can hold 3D information(e.g. data on gene expression, cellproperties, mutant phenotype, etc. fromwhole-mounts or sections) spatiallymapped onto the digital models by usingthe array of voxels as ‘pigeon holes’ in thedatabase. (Guidelines on preparing gene-expression data for entry into this, andsimilar, databases can be found in Ref. 8.)Because the digital models and anatomicalvocabulary are linked, it will be possible toquery the database using combinations ofspatial and textual criteria. It will thus bepossible to find genes with expressionpatterns that are (as defined by user)similar, adjacent or complementary to theexpression domain of a given gene, and todisplay their expression patternsgraphically on the digital models.

We also plan to facilitate links withother databases, in particular the largeamounts of textual gene-expression data inGXD, developed by our colleagues at theJackson Laboratory. Indeed, we arecollaborating with the Jackson Laboratoryto create a ‘mouse gene-expressioninformation resource’ that will provide easyand transparent access to both the MouseAtlas Database and the GXD9. The facilityto visualize and combine experimental datawith information from this resource will,we hope, provide a powerful analytical toolfor gene-function studies.

References

1 Baldock, R.A.B. et al. (1999) The Edinburgh MouseAtlas: basic structure and informatics. InBioinformatics: Databases and Systems. (Letowsky,S. I., ed.), pp. 129–140, Kluwer Academic Publishers

2 Bard, J.B.L. et al. (1998) An internet-accessibledatabase of mouse developmental anatomy based ona systematic nomenclature. Mech. Dev.74, 111–120

3 Theiler, K. (1989) The House Mouse: Atlas of MouseDevelopment, Springer-Verlag

4 Brune, R.M. et al. (1999) A three-dimensional modelof the mouse at embryonic day 9. Dev. Biology216,457–468

5 Kaufman, M.H. et al. (1998) Computer-aided 3-Dreconstruction of serially sectioned mouse embryos.J.Anat. 193, 323–336.

6 Kaufman, M. (1992) The Atlas of MouseDevelopment, Academic Press

7 Ringwald, M. et al. (2000) GXD: intergrated access togene expression data for the laboratory mouse.Trends Genet. 16, 188–190

8 Davidson, D. et al. (1998) Gene expressiondatabases. In In Situ Hybridization, a PracticalApproach, pp. 189–214, IRL Press (OxfordUniversity Press)

9 Ringwald, M. et al. (1994) A database for mousedevelopment. Science265, 2033–2034

Duncan Davidson*†

Jonathan Bard‡

Matthew Kaufman‡

Richard Baldock†

†MRC Human Genetics Unit, WesternGeneral Hospital, Edinburgh, UK EH4 2XU.‡Dept of Biomedical Sciences, HughRobson Building, George Square,Edinburgh, UK EH8 9XD.*e-mail: Duncan.Davidson@hgu.mrc.ac.uk

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Fig. 2.An EmbryoView image of the Theiler stage-14model enables the Atlas model to be displayed as if itwere a whole embryo in a dish, but with key tissueshighlighted; blue, venous system; pink, arterial system;red, outflow tract; yellow, primitive ventricle; green,common atrial chamber; purple, sinus venosus. Thisimage can be rotated by moving the mouse cursor overthe image. Both uncoloured and coloured versions areprovided for each model embryo, the latter displayselected anatomical structures. It is useful to have anEmbryoView window displayed while using theSectionBrowser shown in Fig. 1.

Letters to the Editor

We welcome letters on any topic of interest to geneticists and developmental biologists.Please write to:

The EditorTrends in Genetics, Elsevier Science London, 84 Theobald’s Road, London UK WC1X 8RR.

Tel: +44 (0)20 7611 4400Fax: +44 (0)20 7611 4470; e-mail: tig@current-trends.com