eHistology image and annotation data from the Kaufman Atlas of Mouse Development

eHistology image and annotation data from the Kaufman Atlas of Mouse Development “The Atlas of Mouse Development” by Kaufman is a classic paper atlas that is the de facto standard for the definition of mouse embryo anatomy in the context of standard histological images. We have redigitized the original haematoxylin and eosin–stained tissue sections used for the book at high resolution and transferred the hand-drawn annotations to digital form. We have augmented the annotations with standard ontological assignments (EMAPA anatomy) and made the data freely available via an online viewer (eHistology) and from the University of Edinburgh DataShare archive. The dataset captures and preserves the definitive anatomical knowledge of the original atlas, provides a core image set for deeper community annotation and teaching, and delivers a unique high-quality set of high-resolution histological images through mammalian development for manual and automated analysis. Keywords: embryo; mouse; section; atlas; anatomy; imaging Data Description anatomy ontology [3,4]. The original index for the book was used to develop the primary list of anatomical terms in the ontology, “The Atlas of Mouse Development” [1] is a book detailing the and EMAPA is now recognized as the standard mouse embryo anatomy of mouse embryo development and stands as the ontology used to annotate mouse embryo data including embryo definitive work in the field. The atlas is based on a lifetime of phenotype data [5,6]. work by Kaufman, who established a unique set of histologi- In generating the eHistology Atlas, new images of the histo- cal sections of about 450 mouse embryos, many of which are logical sections were acquired at high resolution, and the an- full serial section-series, from which he selected carefully staged notations have been transferred to a database. These images samples for the histological images within the book. The com- and annotations are now freely available from the eMouseAtlas bination of the histological section series and the printed book web resource as eHistology (Fig. 1) and have been described by represent a unique resource and captures the current under- Graham et al. [7]. The new high-resolution images and the as- standing of classical mouse anatomy. In taxonomic terms, these sociated image coordinates for each annotation are fully freely physical sections are the reference specimens for the definition of available under a Creative Commons CC BY 4.0 licence. In ad- mouse embryo anatomy, and the digitized images with the as- dition, we have an agreement with Elsevier to present the im- sociated annotations are a digital holotype for the definition of ages in a form similar to the original atlas plate layout (the anatomical terms and the progression of mouse embryo devel- web resource), and Elsevier is able to use the new images for opment. In addition, the paper atlas has given rise to the Mouse their own version of an online version if they want to. Here we Atlas programme in Edinburgh [2] and to the EMAPA mouse Received: 18 April 2017; Revised: 6 September 2017; Accepted: 13 December 2017 The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 2 Baldock and Armit Figure 1: Kaufman Atlas eHistology Viewer. A, Screen shot showing the user interface with annotation list. The 3 selected terms showing as a blue “flags” numbers 37, 38, 39 are over the developing kidney. B, The pop-up dialog with extra information on selecting the “37.” C–E, Progressively higher-resolution images corresponding to zooming-in on the image. At full resolution, the pixel spacing is 0.34 × 0.34 microns and reveals cellular architecture and arrangements. describe the dataset of the 937 high-resolution histology images authors concluded that survival depended primarily on institu- with anatomy annotations and how they have been made avail- tional interest and that a strategy dependent on external fund- able for further study and analysis. ing will very likely fail. To ensure long-term preservation of the The motivation for the eHistology resource was to capture image data and supporting annotations, we have therefore reg- the anatomical knowledge in a permanently accessible open istered this dataset with the University of Edinburgh DataShare and digital form delivered with a viewer providing a view of [9] repository [10], with policies registered in OpenDOAR (Direc- the underlying histology data not possible in the printed atlas. tory of Open Access Repositories) [11]. Specifically, the preserva- The high-resolution images provide a rich resource of carefully tion policy includes indefinite preservation of the original data staged mouse histology, which could be used for deeper analysis with format migration to ensure continued readability and ac- of tissue development and as a teaching resource. See Fig. 1 for cessibility. In addition, and for convenience, these data are also an illustration of the resolution now available for these images. hosted in the GigaDB repository [12]. Embryogenesis is a highly dynamic process, and in Fig. 2 we highlight some of the advantages of capturing images at cellular Methods resolution, e.g., the ability to zoom in and morphologically iden- tify mitotically dividing cells and apoptotic cells undergoing pro- Histology grammed cell death. This is simply not possible in the print ver- Details of the mouse strains used, histological sectioning, and sion of the atlas and represents a significant contribution to the staining are provided by Kaufman (1994) [1]. Briefly, the embryos community. were “isolated from spontaneously cycling (C57BL X CBA) F1 hy- All the data are available under a creative commons licence brid females that had been previously mated to genetically sim- (CC BY 4.0). In the future, we envisage the annotations being ex- ilar F1 hybrid males.” The embryos were fixed, dehydrated, em- tended on a tissue-by-tissue basis through community curation. bedded in paraffin wax, and sectioned at 7-micron thickness. The eHistology viewer is open source and is available from the The mounted sections were then stained with haematoxylin Mouse Atlas technical GitHub repository (github.com/ma-tech) and eosin. (eHistology; RRID:SCR 015887). Providing secure and long-term accessibility for research data is a difficult problem. A recent study of the longevity of Slide digitization 375 biomedical resources/databases [8] available on the web in 1997 found that 62.3% had ceased to be available, 14.4% were Digitization of the original histology slides was accomplished static, and only 23.3% were available as an active resource. The using the Olympus DotSlide slide scanner system. Using a Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Mouse embryo anatomy atlas 3 Figure 2: Observing mitosis and apoptosis in cellular resolution eHistology atlas images. A key advantage of capturing histology images at high resolution is the ability to morphologically identify mitotically dividing cells and apoptotic cells in embryo atlas images. A, Zoomed-out view of a coronal image of an E14.5 embryo. B, On the zoomed-in view, neuroblasts in the ventricular zone of the cerebral cortex show intense haematoxylin staining (white arrows), a morphological feature associated with chromosome condensation in mitotically dividing cells. C, On the zoomed-in view, scattered cells in the interdigital zone of the forelimb are pyknotic (black arrows), a morphological feature associated with nuclear condensation. The pyknotic cells additionally show signs of cell shrinkage. These are morphological hallmarks of apoptosis. × 20 objective lens, this generated full-colour images with a we provide a persistent means of accessing the zoom viewer for pixel resolution of 0.34 microns. Calibration was accomplished that image. An example DOI for a single high-resolution image is as part of the digitization process, allowing the inclusion of scale dx.doi.org/10.7488/ds/1232. This link resolves to a specific page bars and the option to measure the distance between 2 points. at the Edinburgh Datashare web resource[14], [15], which in turn In 2 instances (Plate 5 and Plate 14), the original sections could provides a link through to the current URL for the eHistology not be sourced and were presumed lost. In these instances, the viewer. original photographic negatives were used in place of the origi- By starting with a fully persistent DOI, the user will always nal slides to generate cellular-resolution grey-scale images. be able to locate the data and is protected from any change to the hosting domain and URL of the eHistology viewer [16]. For convenience, we also provide an interactive index to the new Annotation and linking to the EMAPA ontology images based on the plate and image designations of the original atlas. Annotation was accomplished using a manual procedure whereby “flags” were positioned on points corresponding to the matching points as used in each plate in the book. The flags were Code availability placed using an editor’s version of the eHistology interface [7]. Each flag was linked to the anatomical term or phrase used in The data are provided in open-standard tif or jpeg image for- the book and also an EMAPA ontology term and an associated mats. All metadata are in plain txt format, and the Supple- Wikipedialink. Thereweremorethan10000 flaglabelsusedto mentary Data are in the Microsoft Excel open xml format annotate the eHistology sections, and linking them to EMAPA xlsx. The code used for the online histology viewer is pro- IDs was achieved through a combination of string matching and vided at the ma-tech GitHub archive, and specifically we use manual assignment of terms [13]. Linking to Wikipedia was ac- the WlzIIPSrv tiled image server and the eAtlasViewer javascript complished using a manual process that utilized parent terms application. in the partonomic ontology tree to find the closest match for a given anatomical term or tissue. Data records Each record has an assigned DOI that resolves to a set of data eHistology viewer files comprising a jpeg or tiff encoded image, Dublin core and Each eHistology image is described in an Edinburgh DataShare other metadata files, and the set of annotations associated with Digital Object Identifier (DOI), and this description includes the the image. The image data volumes range up to 2 Gb, with a URL link to the eHistology viewer for that image. In this way, total volume of 118 GB for the full series in compressed “zip” Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 4 Baldock and Armit Table 1: Listing of the data files available with each dataset File Description license.txt Licence agreement for the data deposited at DataShare providing permissions for distribution and migration as needed—CC BY 4.0. README.txt Short description of the data and data files. citation.txt How to cite use of this particular image. details.txt The text describing the embryo taken from the matching page of the printed atlas and provided in tab-delimited form for reading into a spreadsheet programme. image.tif/image.jpg Full resolution tiff or jpeg formatted image of the histological section. Image.txt Image pixel dimensions and pixel size in microns. terms.txt A tab-delimited table of the annotations for this image providing the Kaufman annotations, location in the image, annotation number, EMAPA ID, and EMAPA term, with synonyms in brackets. url.txt Text providing the URL for the image on the emousetlas.org web resource. Table 2: DataShare Dublin Core elements used for the Kaufman datasets Element Qualifier DCMI Label Input type Mandatory Contributor contributor Depositor name true Contributor other contributor Funder name true Creator creator Data Creator name false Date accessioned Date Date Accessioned date true date available Date Date Available date true Identifier citation identifier Citation citation false Identifier uri identifier Persistent Identifier DOI/handle true Description abstract decription Data Description (abstract) text false Description tableofcontents decription Data Description (TOC) text false Publisher publisher Publisher text true Relation isversionof isVersionOf Relation (Is Version Of) text false Relation isreferencedby isReferencedBy Relation (Is Referenced By) text false Subject subject Subject Keywords text false Subject classification subject Subject Classification Controlled text false Title Title Title text true Title alternative Title Alternative Title text false Type Type Type Controlled text true The DCMI column provides the official Dublin Core term for the element, and Label is the heading for these data on the DataShare metadata listing. format. Table 1 lists the files with each dataset. Each Univer- for the annotation terms have been double-checked, and a se- sity of Edinburgh DataShare submission requires a subset of ries of quality control steps have meant that inspection of the the Dublin Core (dublincore.org) data elements to be completed whole dataset has not revealed any errors. and allows a further set of optional elements; these are de- tailed in Table 2.Table 3 provides a partial listing of the datasets available as an example of the data content. The full listing of Usage Notes all 937 images is provided in the Supplementary Excel format- There are no constraints on the use of the images and asso- ted data file SciDataKaufmanTable3.xlsx and corresponds to all ciated data. The Supplementary Data file lists all samples and of the histology section images of the original atlas for Plate assays—1 for each section image—and also a “source,” which is numbers 2–41. the embryonic mouse specimen used by Kaufman in producing the histological sections. The “source” can be used to identify the set of physical glass slides, archived with the Centre for Re- Technical Validation search Collections of the University of Edinburgh, on which each histological section can be found. In principle, it is possible to The Images and associated data are all validated against the obtain further images of the same or other sections in the se- published atlas, which provides the detail of the genotype, de- ries. “Age” is defined in embryonic days post-coitum, and “stage” fines the histological protocols, and establishes the correct stag- refers to Theiler stage, a morphological staging system used to ing of each embryo against the Theiler criteria. The section further define mouse embryo development. “Position” describes images used in the book are from specific tissue sections iden- the relative position of the section in the embryo, with 0 rep- tified on the sets of microscope slides stored at the MRC Hu- resenting, e.g., the most cranial section in a transverse series man Genetics Unit at the IGMM, University of Edinburgh. Each and 1 denoting the most caudal section. We additionally include section was scanned digitally, then checked by a second cura- details of the pixel resolution of each image, enabling accu- tor to ensure validity. The annotations were originally captured rate measurements to be made on each high-resolution embryo using optical character recognition, and the text and spelling atlas image. were checked by a second curator. All the end-point locations Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Mouse embryo anatomy atlas 5 Table 3: Partial list of data records for the Kaufman Atlas image set Kaufman image Age Stage Orientation Position Stain DOI Plate 02 image a E5.5 7–8 Sagittal H&E http://dx.doi.org/10.7488/ds/393 Plate 02 image b E5.5 7–8 Sagittal H&E http://dx.doi.org/10.7488/ds/394 Plate 02 image c E5.5 7–8 Sagittal H&E http://dx.doi.org/10.7488/ds/395 Plate 02 image d E5.5 7–8 Sagittal H&E http://dx.doi.org/10.7488/ds/396 Plate 03 image a E6.5,7 9,10 Transverse 0.210 H&E http://dx.doi.org/10.7488/ds/397 Plate 03 image b E6.5,7 9,10 Transverse 0.370 H&E http://dx.doi.org/10.7488/ds/398 Plate 03 image c E6.5,7 9,10 Transverse 0.590 H&E http://dx.doi.org/10.7488/ds/399 .. . . . . . .. . . . . . Full table in Supplementary Excel file SciDataKaufmanTable3.xlsx .. . . . . . .. . . . . . .. . . . . . Plate 40l image b E17.5 26 Transverse 0.888 H&E http://dx.doi.org/10.7488/ds/1301 Plate 40l image c E17.5 26 Transverse 0.903 H&E http://dx.doi.org/10.7488/ds/1302 Plate 40l image d E17.5 26 Transverse 0.921 H&E http://dx.doi.org/10.7488/ds/1303 Plate 40l image e E17.5 26 Transverse 0.948 H&E http://dx.doi.org/10.7488/ds/1304 Plate 41 image 41 E17.5 26 Sagittal 0.496 H&E http://dx.doi.org/10.7488/ds/1305 The DOI resolves to a dataset of image data, metadata, and annotations, which can be downloaded individually or combined. Image volumes range up to about 2 Gb, with a total volume for the full set of compressed zip files of 118 Gb. The Position column gives an estimate of the relative distance through the embryo of the individual histology section. The values are between 0 and 1, corresponding to the proportionate distance left-right (sagittal sections), cranial-caudal (transverse sections), and dorsal-ventral (coronal sections). Availability of source code and requirements Abbreviations Project name: eHistology DOI: Digital Object Identifier; H&E: haematoxylin and eosin; Project home page: http://www.emouseatlas.org/emap MRC: Medical Research Council; EMAPA: Edinburgh Mouse Atlas /eHistology/ [RRID:SCR 015887]; https://github.com/ma-tech/ Project Anatomy. eHistologyWebapp Operating system(s): platform independent Competing interests Programming language: The IIP Image server is a Fast CGI mod- ++ ule written in C . The authors declare they have no competing interests in Other requirements: The IIP Image server can be embedded the publication of this data and manuscript. The new high- within a host web server such as Apache, Lighttpd, MyServer, resolution images and the associated image coordinates for each or Nginx. annotation are fully freely available under a Creative Commons License: software—GNU General Public License v2.0; Image CC BY 4.0 licence. We have an agreement with Elsevier to present Data—CC BY 4.0 the images in a form similar to the original atlas plate layout on the eHistology web resource. However, this does not im- pact reuse of the image data and annotation described in this Availability of supporting data manuscript. The image datasets described in this article are available at “Ed- inburgh DataShare” repository as Plates 02–15 (early gestation; E5.5-E8.5), Plates 16–29 (mid-gestation; E8.5-E13.0), Plates 30–41 Funding (late gestation; E13.5-E17.5), and Plates S1-S6 (coronal supple- The MRC Human Genetics Unit Mouse Atlas Programme was ment; E11.5-E15.5) [17]. Each image dataset is provided with all core-funded by the Medical Research Council (Awardee R.A. the information needed to generate the annotated views shown Baldock). on the eHistology website. The data are provided as a series of files, including details.txt—a tab-delimited file with the embryo text description that appears at the top of the printed atlas page; Authors’ contributions image.jpg—full resolution jpeg image of the histological section (in some cases, this is a tif image); terms.txt—a tab-delimited file R.A.B. leads the Mouse Atlas programme that generated these with the annotations for this image, including location of point datasets, designed the dataset submissions to the DataShare annotation (x, y coordinates); and EMAPA ID and EMAPA terms system, and wrote the scripts that provided the upload formats associated with that point. Edinburgh DataShare has provided needed for batch ingest to DataShare. He also wrote the first data DOIs for each of these image datasets, and links to these draft of the manuscript. data DOIs are additionally hosted in GigaDB. An archival copy C.A. is the senior editor for the Mouse Atlas databases, of the GitHub repository with software tools for the eHistology cowrote the manuscript, and has performed much of the quality application is additionally available in GigaDB [12]. control on the datasets. Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 6 Baldock and Armit 6. Mohun T, Adams DJ, Baldock R et al. Deciphering the Mech- Acknowledgements anisms of Developmental Disorders (DMDD): a new pro- The authors would like to acknowledge the critical contribution gramme for phenotyping embryonic lethal mice. Dis Model to the collection, collation, and curation of these data by Liz Mech 2013;6(3):562–6. Graham and Julie Moss and to the development of the data vi- 7. Graham E, Moss J, Burton N et al. The atlas of mouse develop- sualization aspects by Nick Burton. All these are co-authors on ment eHistology resource. Development 2015;142 11:1909– the key citation for this work [7]. The authors would also like to thank the support of the Edina DataShare team, in particular 8. Attwood TK, Agit B, Ellis ABM. Longevity of biological Pauline Ward and Robin Rice. Finally, this work has been funded databases. EMBnet J 2015;21(0):e803. http://dx.doi.org/10. as part of the MRC core-funded Mouse Atlas Programme at the 14806/ej.21.0.803. MRC Human Genetics Unit, Edinburgh. 9. http://datashare.is.ed.ac.uk/. 10. Rice R. Edinburgh datashare - reflections from a data repos- itory manager. Bul Am Soc Info Sci Tech 2014;40(2):39–40. 11. http://www.opendoar.org/find.php?rID =1176&format=full. References 12. Baldock RA, Armit C. Supporting data for “eHistology im- 1. Kaufman MH. The Atlas of Mouse Development. Amster- age and annotation data from the Kaufman Atlas of Mouse dam, the Netherlands: Elsevier Academic Press; 1994. Development.” GigaScience Database 2017. http://dx.doi. 2. Richardson L, Venkataraman S, Stevenson P et al. EMAGE org/10.5524/100365. mouse embryo spatial gene expression database: 2014 up- 13. Richardson L, Moss J, Graham E et al. Developing the eHistol- date. Nucl Acids Res 2014;42(D1):D835–44. ogy Atlas. Database 2015; doi: 10.1093/database/bav105. 3. Hayamizu TF, Wicks MN, Davidson DR et al. EMAP/EMAPA 14. datashare.is.ed.ac.uk/handle/10283/1807. ontology of mouse developmental anatomy: 2013 update. J 15. Graham E, Moss J, Burton N et al. eHistology Kaufman At- Biomed Sem 2013;4(1):15. las Plate 38b image b. University of Edinburgh, College of 4. Hayamizu TF, Baldock RA, Ringwald M. Mouse anatomy on- Medicine and Veterinary Medicine; 2015. http://dx.doi.org/ tologies: enhancements and tools for exploring and integrat- 10.7488/ds/1232. ing biomedical data. Mamm Genome 2015;26(9–10):422–30. 16. www.emouseatlas.org/eAtlasViewer ema/application/ema 5. Brown SD, Moore MW. Towards an encyclopaedia of mam- /kaufman/plate 38b.php?image=b. malian gene function: the International Mouse Phenotyping 17. eHistology Atlas with Kaufman Annotations. https:// Consortium. Dis Model Mech 2012;5(3):289–92. datashare.is.ed.ac.uk/handle/10283/822. Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png GigaScience Oxford University Press

eHistology image and annotation data from the Kaufman Atlas of Mouse Development

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Abstract

“The Atlas of Mouse Development” by Kaufman is a classic paper atlas that is the de facto standard for the definition of mouse embryo anatomy in the context of standard histological images. We have redigitized the original haematoxylin and eosin–stained tissue sections used for the book at high resolution and transferred the hand-drawn annotations to digital form. We have augmented the annotations with standard ontological assignments (EMAPA anatomy) and made the data freely available via an online viewer (eHistology) and from the University of Edinburgh DataShare archive. The dataset captures and preserves the definitive anatomical knowledge of the original atlas, provides a core image set for deeper community annotation and teaching, and delivers a unique high-quality set of high-resolution histological images through mammalian development for manual and automated analysis. Keywords: embryo; mouse; section; atlas; anatomy; imaging Data Description anatomy ontology [3,4]. The original index for the book was used to develop the primary list of anatomical terms in the ontology, “The Atlas of Mouse Development” [1] is a book detailing the and EMAPA is now recognized as the standard mouse embryo anatomy of mouse embryo development and stands as the ontology used to annotate mouse embryo data including embryo definitive work in the field. The atlas is based on a lifetime of phenotype data [5,6]. work by Kaufman, who established a unique set of histologi- In generating the eHistology Atlas, new images of the histo- cal sections of about 450 mouse embryos, many of which are logical sections were acquired at high resolution, and the an- full serial section-series, from which he selected carefully staged notations have been transferred to a database. These images samples for the histological images within the book. The com- and annotations are now freely available from the eMouseAtlas bination of the histological section series and the printed book web resource as eHistology (Fig. 1) and have been described by represent a unique resource and captures the current under- Graham et al. [7]. The new high-resolution images and the as- standing of classical mouse anatomy. In taxonomic terms, these sociated image coordinates for each annotation are fully freely physical sections are the reference specimens for the definition of available under a Creative Commons CC BY 4.0 licence. In ad- mouse embryo anatomy, and the digitized images with the as- dition, we have an agreement with Elsevier to present the im- sociated annotations are a digital holotype for the definition of ages in a form similar to the original atlas plate layout (the anatomical terms and the progression of mouse embryo devel- web resource), and Elsevier is able to use the new images for opment. In addition, the paper atlas has given rise to the Mouse their own version of an online version if they want to. Here we Atlas programme in Edinburgh [2] and to the EMAPA mouse Received: 18 April 2017; Revised: 6 September 2017; Accepted: 13 December 2017 The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 2 Baldock and Armit Figure 1: Kaufman Atlas eHistology Viewer. A, Screen shot showing the user interface with annotation list. The 3 selected terms showing as a blue “flags” numbers 37, 38, 39 are over the developing kidney. B, The pop-up dialog with extra information on selecting the “37.” C–E, Progressively higher-resolution images corresponding to zooming-in on the image. At full resolution, the pixel spacing is 0.34 × 0.34 microns and reveals cellular architecture and arrangements. describe the dataset of the 937 high-resolution histology images authors concluded that survival depended primarily on institu- with anatomy annotations and how they have been made avail- tional interest and that a strategy dependent on external fund- able for further study and analysis. ing will very likely fail. To ensure long-term preservation of the The motivation for the eHistology resource was to capture image data and supporting annotations, we have therefore reg- the anatomical knowledge in a permanently accessible open istered this dataset with the University of Edinburgh DataShare and digital form delivered with a viewer providing a view of [9] repository [10], with policies registered in OpenDOAR (Direc- the underlying histology data not possible in the printed atlas. tory of Open Access Repositories) [11]. Specifically, the preserva- The high-resolution images provide a rich resource of carefully tion policy includes indefinite preservation of the original data staged mouse histology, which could be used for deeper analysis with format migration to ensure continued readability and ac- of tissue development and as a teaching resource. See Fig. 1 for cessibility. In addition, and for convenience, these data are also an illustration of the resolution now available for these images. hosted in the GigaDB repository [12]. Embryogenesis is a highly dynamic process, and in Fig. 2 we highlight some of the advantages of capturing images at cellular Methods resolution, e.g., the ability to zoom in and morphologically iden- tify mitotically dividing cells and apoptotic cells undergoing pro- Histology grammed cell death. This is simply not possible in the print ver- Details of the mouse strains used, histological sectioning, and sion of the atlas and represents a significant contribution to the staining are provided by Kaufman (1994) [1]. Briefly, the embryos community. were “isolated from spontaneously cycling (C57BL X CBA) F1 hy- All the data are available under a creative commons licence brid females that had been previously mated to genetically sim- (CC BY 4.0). In the future, we envisage the annotations being ex- ilar F1 hybrid males.” The embryos were fixed, dehydrated, em- tended on a tissue-by-tissue basis through community curation. bedded in paraffin wax, and sectioned at 7-micron thickness. The eHistology viewer is open source and is available from the The mounted sections were then stained with haematoxylin Mouse Atlas technical GitHub repository (github.com/ma-tech) and eosin. (eHistology; RRID:SCR 015887). Providing secure and long-term accessibility for research data is a difficult problem. A recent study of the longevity of Slide digitization 375 biomedical resources/databases [8] available on the web in 1997 found that 62.3% had ceased to be available, 14.4% were Digitization of the original histology slides was accomplished static, and only 23.3% were available as an active resource. The using the Olympus DotSlide slide scanner system. Using a Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Mouse embryo anatomy atlas 3 Figure 2: Observing mitosis and apoptosis in cellular resolution eHistology atlas images. A key advantage of capturing histology images at high resolution is the ability to morphologically identify mitotically dividing cells and apoptotic cells in embryo atlas images. A, Zoomed-out view of a coronal image of an E14.5 embryo. B, On the zoomed-in view, neuroblasts in the ventricular zone of the cerebral cortex show intense haematoxylin staining (white arrows), a morphological feature associated with chromosome condensation in mitotically dividing cells. C, On the zoomed-in view, scattered cells in the interdigital zone of the forelimb are pyknotic (black arrows), a morphological feature associated with nuclear condensation. The pyknotic cells additionally show signs of cell shrinkage. These are morphological hallmarks of apoptosis. × 20 objective lens, this generated full-colour images with a we provide a persistent means of accessing the zoom viewer for pixel resolution of 0.34 microns. Calibration was accomplished that image. An example DOI for a single high-resolution image is as part of the digitization process, allowing the inclusion of scale dx.doi.org/10.7488/ds/1232. This link resolves to a specific page bars and the option to measure the distance between 2 points. at the Edinburgh Datashare web resource[14], [15], which in turn In 2 instances (Plate 5 and Plate 14), the original sections could provides a link through to the current URL for the eHistology not be sourced and were presumed lost. In these instances, the viewer. original photographic negatives were used in place of the origi- By starting with a fully persistent DOI, the user will always nal slides to generate cellular-resolution grey-scale images. be able to locate the data and is protected from any change to the hosting domain and URL of the eHistology viewer [16]. For convenience, we also provide an interactive index to the new Annotation and linking to the EMAPA ontology images based on the plate and image designations of the original atlas. Annotation was accomplished using a manual procedure whereby “flags” were positioned on points corresponding to the matching points as used in each plate in the book. The flags were Code availability placed using an editor’s version of the eHistology interface [7]. Each flag was linked to the anatomical term or phrase used in The data are provided in open-standard tif or jpeg image for- the book and also an EMAPA ontology term and an associated mats. All metadata are in plain txt format, and the Supple- Wikipedialink. Thereweremorethan10000 flaglabelsusedto mentary Data are in the Microsoft Excel open xml format annotate the eHistology sections, and linking them to EMAPA xlsx. The code used for the online histology viewer is pro- IDs was achieved through a combination of string matching and vided at the ma-tech GitHub archive, and specifically we use manual assignment of terms [13]. Linking to Wikipedia was ac- the WlzIIPSrv tiled image server and the eAtlasViewer javascript complished using a manual process that utilized parent terms application. in the partonomic ontology tree to find the closest match for a given anatomical term or tissue. Data records Each record has an assigned DOI that resolves to a set of data eHistology viewer files comprising a jpeg or tiff encoded image, Dublin core and Each eHistology image is described in an Edinburgh DataShare other metadata files, and the set of annotations associated with Digital Object Identifier (DOI), and this description includes the the image. The image data volumes range up to 2 Gb, with a URL link to the eHistology viewer for that image. In this way, total volume of 118 GB for the full series in compressed “zip” Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 4 Baldock and Armit Table 1: Listing of the data files available with each dataset File Description license.txt Licence agreement for the data deposited at DataShare providing permissions for distribution and migration as needed—CC BY 4.0. README.txt Short description of the data and data files. citation.txt How to cite use of this particular image. details.txt The text describing the embryo taken from the matching page of the printed atlas and provided in tab-delimited form for reading into a spreadsheet programme. image.tif/image.jpg Full resolution tiff or jpeg formatted image of the histological section. Image.txt Image pixel dimensions and pixel size in microns. terms.txt A tab-delimited table of the annotations for this image providing the Kaufman annotations, location in the image, annotation number, EMAPA ID, and EMAPA term, with synonyms in brackets. url.txt Text providing the URL for the image on the emousetlas.org web resource. Table 2: DataShare Dublin Core elements used for the Kaufman datasets Element Qualifier DCMI Label Input type Mandatory Contributor contributor Depositor name true Contributor other contributor Funder name true Creator creator Data Creator name false Date accessioned Date Date Accessioned date true date available Date Date Available date true Identifier citation identifier Citation citation false Identifier uri identifier Persistent Identifier DOI/handle true Description abstract decription Data Description (abstract) text false Description tableofcontents decription Data Description (TOC) text false Publisher publisher Publisher text true Relation isversionof isVersionOf Relation (Is Version Of) text false Relation isreferencedby isReferencedBy Relation (Is Referenced By) text false Subject subject Subject Keywords text false Subject classification subject Subject Classification Controlled text false Title Title Title text true Title alternative Title Alternative Title text false Type Type Type Controlled text true The DCMI column provides the official Dublin Core term for the element, and Label is the heading for these data on the DataShare metadata listing. format. Table 1 lists the files with each dataset. Each Univer- for the annotation terms have been double-checked, and a se- sity of Edinburgh DataShare submission requires a subset of ries of quality control steps have meant that inspection of the the Dublin Core (dublincore.org) data elements to be completed whole dataset has not revealed any errors. and allows a further set of optional elements; these are de- tailed in Table 2.Table 3 provides a partial listing of the datasets available as an example of the data content. The full listing of Usage Notes all 937 images is provided in the Supplementary Excel format- There are no constraints on the use of the images and asso- ted data file SciDataKaufmanTable3.xlsx and corresponds to all ciated data. The Supplementary Data file lists all samples and of the histology section images of the original atlas for Plate assays—1 for each section image—and also a “source,” which is numbers 2–41. the embryonic mouse specimen used by Kaufman in producing the histological sections. The “source” can be used to identify the set of physical glass slides, archived with the Centre for Re- Technical Validation search Collections of the University of Edinburgh, on which each histological section can be found. In principle, it is possible to The Images and associated data are all validated against the obtain further images of the same or other sections in the se- published atlas, which provides the detail of the genotype, de- ries. “Age” is defined in embryonic days post-coitum, and “stage” fines the histological protocols, and establishes the correct stag- refers to Theiler stage, a morphological staging system used to ing of each embryo against the Theiler criteria. The section further define mouse embryo development. “Position” describes images used in the book are from specific tissue sections iden- the relative position of the section in the embryo, with 0 rep- tified on the sets of microscope slides stored at the MRC Hu- resenting, e.g., the most cranial section in a transverse series man Genetics Unit at the IGMM, University of Edinburgh. Each and 1 denoting the most caudal section. We additionally include section was scanned digitally, then checked by a second cura- details of the pixel resolution of each image, enabling accu- tor to ensure validity. The annotations were originally captured rate measurements to be made on each high-resolution embryo using optical character recognition, and the text and spelling atlas image. were checked by a second curator. All the end-point locations Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Mouse embryo anatomy atlas 5 Table 3: Partial list of data records for the Kaufman Atlas image set Kaufman image Age Stage Orientation Position Stain DOI Plate 02 image a E5.5 7–8 Sagittal H&E http://dx.doi.org/10.7488/ds/393 Plate 02 image b E5.5 7–8 Sagittal H&E http://dx.doi.org/10.7488/ds/394 Plate 02 image c E5.5 7–8 Sagittal H&E http://dx.doi.org/10.7488/ds/395 Plate 02 image d E5.5 7–8 Sagittal H&E http://dx.doi.org/10.7488/ds/396 Plate 03 image a E6.5,7 9,10 Transverse 0.210 H&E http://dx.doi.org/10.7488/ds/397 Plate 03 image b E6.5,7 9,10 Transverse 0.370 H&E http://dx.doi.org/10.7488/ds/398 Plate 03 image c E6.5,7 9,10 Transverse 0.590 H&E http://dx.doi.org/10.7488/ds/399 .. . . . . . .. . . . . . Full table in Supplementary Excel file SciDataKaufmanTable3.xlsx .. . . . . . .. . . . . . .. . . . . . Plate 40l image b E17.5 26 Transverse 0.888 H&E http://dx.doi.org/10.7488/ds/1301 Plate 40l image c E17.5 26 Transverse 0.903 H&E http://dx.doi.org/10.7488/ds/1302 Plate 40l image d E17.5 26 Transverse 0.921 H&E http://dx.doi.org/10.7488/ds/1303 Plate 40l image e E17.5 26 Transverse 0.948 H&E http://dx.doi.org/10.7488/ds/1304 Plate 41 image 41 E17.5 26 Sagittal 0.496 H&E http://dx.doi.org/10.7488/ds/1305 The DOI resolves to a dataset of image data, metadata, and annotations, which can be downloaded individually or combined. Image volumes range up to about 2 Gb, with a total volume for the full set of compressed zip files of 118 Gb. The Position column gives an estimate of the relative distance through the embryo of the individual histology section. The values are between 0 and 1, corresponding to the proportionate distance left-right (sagittal sections), cranial-caudal (transverse sections), and dorsal-ventral (coronal sections). Availability of source code and requirements Abbreviations Project name: eHistology DOI: Digital Object Identifier; H&E: haematoxylin and eosin; Project home page: http://www.emouseatlas.org/emap MRC: Medical Research Council; EMAPA: Edinburgh Mouse Atlas /eHistology/ [RRID:SCR 015887]; https://github.com/ma-tech/ Project Anatomy. eHistologyWebapp Operating system(s): platform independent Competing interests Programming language: The IIP Image server is a Fast CGI mod- ++ ule written in C . The authors declare they have no competing interests in Other requirements: The IIP Image server can be embedded the publication of this data and manuscript. The new high- within a host web server such as Apache, Lighttpd, MyServer, resolution images and the associated image coordinates for each or Nginx. annotation are fully freely available under a Creative Commons License: software—GNU General Public License v2.0; Image CC BY 4.0 licence. We have an agreement with Elsevier to present Data—CC BY 4.0 the images in a form similar to the original atlas plate layout on the eHistology web resource. However, this does not im- pact reuse of the image data and annotation described in this Availability of supporting data manuscript. The image datasets described in this article are available at “Ed- inburgh DataShare” repository as Plates 02–15 (early gestation; E5.5-E8.5), Plates 16–29 (mid-gestation; E8.5-E13.0), Plates 30–41 Funding (late gestation; E13.5-E17.5), and Plates S1-S6 (coronal supple- The MRC Human Genetics Unit Mouse Atlas Programme was ment; E11.5-E15.5) [17]. Each image dataset is provided with all core-funded by the Medical Research Council (Awardee R.A. the information needed to generate the annotated views shown Baldock). on the eHistology website. The data are provided as a series of files, including details.txt—a tab-delimited file with the embryo text description that appears at the top of the printed atlas page; Authors’ contributions image.jpg—full resolution jpeg image of the histological section (in some cases, this is a tif image); terms.txt—a tab-delimited file R.A.B. leads the Mouse Atlas programme that generated these with the annotations for this image, including location of point datasets, designed the dataset submissions to the DataShare annotation (x, y coordinates); and EMAPA ID and EMAPA terms system, and wrote the scripts that provided the upload formats associated with that point. Edinburgh DataShare has provided needed for batch ingest to DataShare. He also wrote the first data DOIs for each of these image datasets, and links to these draft of the manuscript. data DOIs are additionally hosted in GigaDB. An archival copy C.A. is the senior editor for the Mouse Atlas databases, of the GitHub repository with software tools for the eHistology cowrote the manuscript, and has performed much of the quality application is additionally available in GigaDB [12]. control on the datasets. Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018 6 Baldock and Armit 6. Mohun T, Adams DJ, Baldock R et al. Deciphering the Mech- Acknowledgements anisms of Developmental Disorders (DMDD): a new pro- The authors would like to acknowledge the critical contribution gramme for phenotyping embryonic lethal mice. Dis Model to the collection, collation, and curation of these data by Liz Mech 2013;6(3):562–6. Graham and Julie Moss and to the development of the data vi- 7. Graham E, Moss J, Burton N et al. The atlas of mouse develop- sualization aspects by Nick Burton. All these are co-authors on ment eHistology resource. Development 2015;142 11:1909– the key citation for this work [7]. The authors would also like to thank the support of the Edina DataShare team, in particular 8. Attwood TK, Agit B, Ellis ABM. Longevity of biological Pauline Ward and Robin Rice. Finally, this work has been funded databases. EMBnet J 2015;21(0):e803. http://dx.doi.org/10. as part of the MRC core-funded Mouse Atlas Programme at the 14806/ej.21.0.803. MRC Human Genetics Unit, Edinburgh. 9. http://datashare.is.ed.ac.uk/. 10. Rice R. Edinburgh datashare - reflections from a data repos- itory manager. Bul Am Soc Info Sci Tech 2014;40(2):39–40. 11. http://www.opendoar.org/find.php?rID =1176&format=full. References 12. Baldock RA, Armit C. Supporting data for “eHistology im- 1. Kaufman MH. The Atlas of Mouse Development. Amster- age and annotation data from the Kaufman Atlas of Mouse dam, the Netherlands: Elsevier Academic Press; 1994. Development.” GigaScience Database 2017. http://dx.doi. 2. Richardson L, Venkataraman S, Stevenson P et al. EMAGE org/10.5524/100365. mouse embryo spatial gene expression database: 2014 up- 13. Richardson L, Moss J, Graham E et al. Developing the eHistol- date. Nucl Acids Res 2014;42(D1):D835–44. ogy Atlas. Database 2015; doi: 10.1093/database/bav105. 3. Hayamizu TF, Wicks MN, Davidson DR et al. EMAP/EMAPA 14. datashare.is.ed.ac.uk/handle/10283/1807. ontology of mouse developmental anatomy: 2013 update. J 15. Graham E, Moss J, Burton N et al. eHistology Kaufman At- Biomed Sem 2013;4(1):15. las Plate 38b image b. University of Edinburgh, College of 4. Hayamizu TF, Baldock RA, Ringwald M. Mouse anatomy on- Medicine and Veterinary Medicine; 2015. http://dx.doi.org/ tologies: enhancements and tools for exploring and integrat- 10.7488/ds/1232. ing biomedical data. Mamm Genome 2015;26(9–10):422–30. 16. www.emouseatlas.org/eAtlasViewer ema/application/ema 5. Brown SD, Moore MW. Towards an encyclopaedia of mam- /kaufman/plate 38b.php?image=b. malian gene function: the International Mouse Phenotyping 17. eHistology Atlas with Kaufman Annotations. https:// Consortium. Dis Model Mech 2012;5(3):289–92. datashare.is.ed.ac.uk/handle/10283/822. Downloaded from https://academic.oup.com/gigascience/article-abstract/7/2/1/4768197 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Published: Feb 1, 2018

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