WormGUIDES: an interactive single cell developmental atlas and tool for collaborative multidimensional data exploration

Abstract

Background: Imaging and image analysis advances are yielding increasingly complete and complicated records of cellular events in tissues and whole embryos. The ability to follow hundreds to thousands of cells at the individual level demands a spatio-temporal data infrastructure: tools to assemble and collate knowledge about development spatially in a manner analogous to geographic information systems (GIS). Just as GIS indexes items or events based on their spatio-temporal or 4D location on the Earth these tools would organize knowledge based on location within the tissues or embryos. Developmental processes are highly context-specific, but the complexity of the 4D environment in which they unfold is a barrier to assembling an understanding of any particular process from diverse sources of information. In the same way that GIS aids the understanding and use of geo-located large data sets, software can, with a proper frame of reference, allow large biological data sets to be understood spatially. Intuitive tools are needed to navigate the spatial structure of complex tissue, collate large data sets and existing knowledge with this spatial structure and help users derive hypotheses about developmental mechanisms.

Results: Toward this goal we have developed WormGUIDES, a mobile application that presents a 4D developmental atlas for Caenorhabditis elegans. The WormGUIDES mobile app enables users to navigate a 3D model depicting the nuclear positions of all cells in the developing embryo. The identity of each cell can be queried with a tap, and community databases searched for available information about that cell. Information about ancestry, fate and gene expression can be used to label cells and craft customized visualizations that highlight cells as potential players in an event of interest. Scenes are easily saved, shared and published to other WormGUIDES users. The mobile app is available for Android and iOS platforms.

Conclusion: WormGUIDES provides an important tool for examining developmental processes and developing mechanistic hypotheses about their control. Critically, it provides the typical end user with an intuitive interface for developing and sharing custom visualizations of developmental processes. Equally important, because users can select cells based on their position and search for information about them, the app also serves as a spatially organized index into the large body of knowledge available to the C. elegans community online. Moreover, the app can be used to create and publish the result of exploration: interactive content that brings other researchers and students directly to the spatio-temporal point of insight. Ultimately the app will incorporate a detailed time lapse record of cell shape, beginning with neurons. This will add the key ability to navigate and understand the developmental events that result in the coordinated and precise emergence of anatomy, particularly the wiring of the nervous system.

Fig. 1

WormGUIDES vision and input data. The goal of WormGUIDES is to enable novel visual exploration of development by providing an intuitive interface for exploring single cell level records of embryonic development in 4D. WormGUIDES also provides a spatial index into community knowledge bases by enabling users to quickly search for information on cells they have identified via 4D exploration. Detailed cell positions and (in future releases) cell morphology are combined with available knowledge to create a convenient way to navigate views of development. The expectation is that this ability to understand cells in the context of the embryo will enable a deeper understanding of how complex processes, particularly neural development, unfold

Fig. 2

WormGUIDES app user interface. a. Interface overview showing the interactive nuclear position model with cells colored by tissue fate. b. Information pop up that appears upon tapping on a cell. This pop up shows the cell name. Upon expanding it with a tap the fate description of terminal cells is displayed. The cell can be recolored by tapping the magnifying glass,or a search for that cell can be executed against online knowledgebases. c. The search interface allows users to intuitively control the 3D model’s colors. Text searches can be executed against systematic names, terminal cell names and fate descriptions as well as online searches against WormBase gene expression information. d. The sharing panel which allows the user to share a screen shot or a scene definition that can be loaded by other app users

Fig. 3

Customizing visualization with the search inteface. a. A lineage color scheme with each founder cell lineage in a different color. b. Early ~500 cell view of embryo highlighting neuronal subtypes from left and ventral views. c. A view of the same color scheme, approximately two hours later showing rearrangement of cells into more tightly organized neural tissue. d. Results of a gene search for pha-4 showing the pharynx primordium and gut cells. e. Overlapping colored sublineages, each highlighting hypodermal fate using a different method, and a close up of the color key corresponding to the embyro illustrate how overlapping color schemes are rendered by striping the colors that apply to a cell

Fig. 4

Toward integration of neural morphology into WormGUIDES. a. Schematic of the neuron shape characterization strategy. Multiple strains with different subsets of labeled neurons are lineaged and segmented. Nuclear positions are used to align data to a single reference coordinate system. b. Key to lim-4 expressing cells identities. c. A time lapse 3D reconstruction of pairs of left right symmetric neurons expressing lim-4 imaged using a diSPIM system. Close, difficult to resolve clusters of cells are segmented as a single object. Nuclei are rendered as small gray spheres. Cell bodies are colored to show left right symmetry. A series of images of the reconstruction spanning 40 min is shown. Time 0 is an arbitrary point where lim-4 expression is clearly visible; Time 40 is approximately 10 min before twitching begins. Cell lineage and cell shape are semi-automatically segmented and tracked