Jonathan Bard

An ontology for cell types

We describe an ontology for cell types that covers the prokaryotic, fungal, animal and plant worlds. It includes over 680 cell types. These cell types are classified under several generic categories and are organized as a directed acyclic graph. The ontology is available in the formats adopted by the Open Biological Ontologies umbrella and is designed to be used in the context of model organism genome and other biological databases. The ontology is freely available at http://obo.sourceforge.net/ and can be viewed using standard ontology visualization tools such as OBO-Edit and COBrA.

ONTOLOGIES IN BIOLOGY: DESIGN, APPLICATIONS AND FUTURE CHALLENGES

Biological knowledge is inherently complex and so cannot readily be integrated into existing databases of molecular (for example, sequence) data. An ontology is a formal way of representing knowledge in which concepts are described both by their meaning and their relationship to each other. Unique identifiers that are associated with each concept in biological ontologies (bio-ontologies) can be used for linking to and querying molecular databases. This article reviews the principal bio-ontologies and the current issues in their design and development: these include the ability to query across databases and the problems of constructing ontologies that describe complex knowledge, such as phenotypes.

EMAP and EMAGE: a framework for understanding spatially organized data.

The Edinburgh Mouse Atlas Project (EMAP) is a time-series of mouse-embryo volumetric models. The models provide a context-free spatial framework onto which structural interpretations and experimental data can be mapped. This enables collation, comparison, and query of complex spatial patterns with respect to each other and with respect to known or hypothesized structure. The atlas also includes a time-dependent anatomical ontology and mapping between the ontology and the spatial models in the form of delineated anatomical regions or tissues. The models provide a natural, graphical context for browsing and visualizing complex data.The Edinburgh Mouse Atlas Gene-Expression Database (EMAGE) is one of the first applications of the EMAP framework and provides a spatially mapped gene-expression database with associated tools for data mapping, submission, and query. In this article, we describe the underlying principles of the Atlas and the gene-expression database, and provide a practical introduction to the use of the EMAP and EMAGE tools, including use of new techniques for whole body gene-expression data capture and mapping.

An internet-accessible database of mouse developmental anatomy based on a systematic nomenclature

This paper reports an internet-accessible database of mouse developmental anatomy (DMDA) that currently holds a hierarchy of the names and synonyms of the tissues in the first 22 Theiler stages of development (E1-E13.5), together with other appropriate information. The purposes of the database are to provide, first, a nomenclature for analyzing normal and mutant mouse anatomy, and second a language for inputting, storing and querying gene-expression and other spatially organized data. DMDA currently contains some 6900 named and staged tissues (e.g. 360 and 1161 tissues in Theiler stage (TS) 14 (E9) and TS22 (E13.5) embryos). DMDA will be extended to include further lineage and other data when it becomes available. The database can be interactively accessed over the internet using either a Java or a non-Java WWW browser at http://genex.hgu.mrc.ac.uk/.

Morphogenesis : the cellular and molecular processes of developmental anatomy

Preface Acknowledgements 1. Introduction 2. Background 3. Case studies 4. The molecular basis of morphogenesis 5. The morphogenetic properties of mesenchyme 6. The epithelial repertoire 7. A dynamic framework for morphogenesis 8. Pulling together some threads Appendices References Index.

How well does Turing's theory of morphogenesis work?

Abstract In 1952 Turing published a paper which showed how under restricted conditions a class of chemical reactions could give biological patterns in diffusion-coupled cells. Although this theory has been much discussed, little has been learnt about the range and type of pattern it can generate. In order to do this and to see how stable the patterns are, we have examined the system in detail and written a computer program to simulate Turings kinetics for two morphogens over various assemblies of cells. We find that on one-dimensional lines of cells, patterns can indeed be produced and that the chemical wavelengths follow all of Turings predictions. The results show that stable repeating peaks of chemical concentration of periodicity 2–20 cells can be obtained in embryos in periods of time of less than an hour. We do find however that these patterns are not reliable: small variations in initial conditions give small but significant changes in the number and positions of observed peaks. Similar results are observed in two-dimensional assemblies of cells. On rectangles, random blotches are observed whose position cannot be reliably predicted. On cylinders whose circumference is less than the chemical wavelength, annular stripes are produced. For larger cylinders, blotches that lie very approximately on helices are generated; again sharp prediction of the detailed pattern is impossible. The significance of these results for the developing embryo is discussed. We conclude that Turing kinetics, at least in the simple cases that we have studied, are too unreliable to serve as the generating mechanism for features such as digits which are characterized by a consistent number of units. The theory is however more than adequate by these criteria to specify less well-defined developing patterns such as those of hair follicles or leaf organization. It is emphasized however that the Turing theory is quite unable to generate regulative systems, only mosaicpatterns can be produced.

A model for generating aspects of zebra and other mammalian coat patterns

Abstract A model is put forward which is capable of generating chemical maps whose concentration contours are similar to the patterns seen on the flanks of zebras, cats and other mammals. The model derives from the reaction-diffusion kinetics invented by Turing (1952) and it is assumed that the necessary molecular apparatus is present in each cell of a two-dimensional array and that the cells are in diffusion contact. The model was expressed in differential equation form and solved digitally under a range of different initial, boundary and other conditions. The main forms of pattern that the model generated were spots of variable complexity, rings, and both vertical and horizontal stripes. If morphogen concentration levels are assumed to act as melanin-production switches, then a common basic mechanism is capable of generating a variety of skin patterns. Simple spots such as those found in the fallow deer or the serval, F. serval , are generated if the kinetics are initiated simultaneously in each cell and interpretation depends only on the presence or absence of morphogen, which is assumed for the deer to be an activator and for the cat a suppressor of pigment formation. The reticulated pattern of the giraffe is generated if there is a single high-value threshold. Complex spots typical of the leopards can be produced if there are different concentration thresholds for different colours. Rings of pattern typical of those found on cat tails are generated if the cellular array is a very narrow cylinder. Horizontal stripes are generated if the kinetics in each cell are initiated by a diffusion gradient whose source is the dorsal line of cells and these stripes may break up into spots to give a pattern very similar to that of, for example, the fishing cat, F. viverina . The vertical stripes of the caffre cat, F. caffra , or the zebras are formed if the kinetics are initiated by a vertically-moving constant-velocity wave which also allows morphogen diffusion between previously uncoupled cells. Thus far, the mechanism has generated neither the triradii that are commonly found on forelimbs nor the rings often observed on mammalian limbs. It does however incorporate the randomness that characterizes skin pattern, its operation is of the scale required in embryogenesis, it can be made stable to growth and it can explain certain degenerate patterns. Analysis of a spotted zebra in the light of the model provides evidence that zebra stripes arise from the inhibition rather than the stimulation of melanin; their pattern is thus of white stripes on a black background.

8 The Development of the Kidney

Publisher Summary This chapter describes the earlier stages of development of the vertebrate metanephric kidney. It focuses on the mouse and descriptive morphology is used for considering both molecular mechanisms, underpinning kidney morphogenesis and differentiation, and the ways in which these processes can go awry and lead to congenital kidney disorders—particularly in humans. The mature kidney is a fairly complex organ attached to an arterial input vessel and two output vessels, the vein and the ureter. Inside, the artery and vein are connected by a complex network of capillaries that invade a large number of glomeruli, the proximal entrance to nephrons, which are filtration units that link to an arborized collecting-duct system that drains into the ureter. The ability of the kidney and isolated metanephrogenic mesenchyme, to develop in culture means that the developing tissues can be subjected to a wide variety of experimental procedures designed to investigate their molecular and cellular properties and to test hypotheses about developmental mechanisms.

The growth and morphogenesis of the early mouse mandible: a quantitative analysis

Three‐dimensional reconstruction and BrdU incorporation have been used to quantify the development and growth of the mouse mandible and to analyse its relationship to Meckels cartilage and the molar teeth. The mandible anlage is first histologically detectable at E13.5 as paired plates of osteoid tissue within condensed mesenchyme (∼0.9 mm long and ∼0.36 mm deep) that are lateral to the two arms of Meckels cartilage. Over the next 3 days, each plate lengthens to ∼3.6 mm, and extends medially at its superior and inferior edges, folding over to enclose the alveolar nerve and Meckels cartilage and producing additional processes that form the molar tooth sockets (E15.5). At around E15.5, the first molar tooth socket forms from two processes that extend from the medial and distal parts of the mandible to surround the tooth. By E16.5, this process is complete in the distal region where Meckels cartilage is beginning to degenerate. Mandible ossification begins at E14 with proliferation restricted to the outer surface. BrdU incorporation rates are particularly high at the proximal and distal ends where lengthening occurs, and at the superior and inferior edges as they extend medially to surround Meckels cartilage. Incorporation rates slow at the distal ends of each mandible at E16.5 as they approach each other at the symphysis. The results indicate that the mandible mainly grows at its periphery, and the pattern of mandibular growth and morphogenesis suggests that these processes are mainly directed and constrained by paracrine signalling from Meckels cartilage and the tooth buds.

Tetraploidy in mice, embryonic cell number, and the grain of the developmental map

Tetraploid mice prepared by electrofusion develop for up to 14 days in utero. The embryos are essentially normal save that the forebrain and its associated tissues fail to develop properly. Here, we report measurements of cell counts in tissues and volume measurements of tetraploid and control embryos together with observations on the morphology of tetraploid embryos. The results show that the tetraploid embryos are about 85% normal size, but have only a little under half the number of cells of control embryos, with their nuclei being about twice the size of those of diploid cells. Close examination of sectioned material, in contrast, showed that tetraploid morphology and morphogenesis were indistinguishable from those of controls, except in forebrain-associated material. This conclusion gives some insight into an important developmental question, how fine can the developmental map be for normal cellular differentiation to proceed? As tetraploids have only about half the expected number of cells, the ability of these embryos to develop normally in all regions except the forebrain and its derivatives argues that pattern formation mechanisms can cope with the abnormally small number of cells in all regions except the forebrain. The results as a whole argue for size regulation in mammalian embryos being achieved by assaying absolute size rather than counting cell numbers.