title: An ensemble-averaged, cell density-based digital model of zebrafish embryo development derived from light-sheet microscopy data with single-cell resolution.
abstract: A new era in developmental biology has been ushered in by recent advances in the quantitative imaging of all-cell morphogenesis in living organisms. Here we have developed a light-sheet fluorescence microscopy-based framework with single-cell resolution for identification and characterization of subtle phenotypical changes of millimeter-sized organisms. Such a comparative study requires analyses of entire ensembles to be able to distinguish sample-to-sample variations from definitive phenotypical changes. We present a kinetic digital model of zebrafish embryos up to 16 h of development. The model is based on the precise overlay and averaging of data taken on multiple individuals and describes the cell density and its migration direction at every point in time. Quantitative metrics for multi-sample comparative studies have been introduced to analyze developmental variations within the ensemble. The digital model may serve as a canvas on which the behavior of cellular subpopulations can be studied. As an example, we have investigated cellular rearrangements during germ layer formation at the onset of gastrulation. A comparison of the one-eyed pinhead (oep) mutant with the digital model of the wild-type embryo reveals its abnormal development at the onset of gastrulation, many hours before changes are obvious to the eye.
authors.affiliation: 1] Institute of Applied Physics, Karlsruhe Institute of Technology, Wolfgang-Gaede-Str. 1, 76131 Karlsruhe, Germany [2] Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany [3] European Zebrafish Resource Centre, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Andrei Y
authors.initials: AY
authors.lastname: Kobitski
authors.affiliation: 1] Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany [2] European Zebrafish Resource Centre, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Otte
authors.affiliation: 1] Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany [2] European Zebrafish Resource Centre, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Masanari
authors.initials: M
authors.lastname: Takamiya
authors.affiliation: Institute of Applied Physics, Karlsruhe Institute of Technology, Wolfgang-Gaede-Str. 1, 76131 Karlsruhe, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schäfer
authors.affiliation: Institute of Applied Physics, Karlsruhe Institute of Technology, Wolfgang-Gaede-Str. 1, 76131 Karlsruhe, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Mertes
authors.affiliation: Institute for Applied Computer Science, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegmaier
authors.affiliation: 1] Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany [2] European Zebrafish Resource Centre, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Sepand
authors.initials: S
authors.lastname: Rastegar
authors.affiliation: Institute for Data Processing and Electronics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rindone
authors.affiliation: Institute for Data Processing and Electronics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hartmann
authors.affiliation: Institute for Data Processing and Electronics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Stotzka
authors.affiliation: Steinbuch Centre for Computing, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Ariel
authors.initials: A
authors.lastname: García
authors.affiliation: Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Jos
authors.initials: J
authors.lastname: van Wezel
authors.affiliation: Institute for Applied Computer Science, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Mikut
authors.affiliation: 1] Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany [2] European Zebrafish Resource Centre, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Strähle
authors.affiliation: 1] Institute of Applied Physics, Karlsruhe Institute of Technology, Wolfgang-Gaede-Str. 1, 76131 Karlsruhe, Germany [2] Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany [3] European Zebrafish Resource Centre, Karlsruhe Institute of Technology, Post Office Box 3640, 76021 Karlsruhe, Germany [4] Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: G Ulrich
authors.initials: GU
authors.lastname: Nienhaus
mesh_terms: D000818:Animals; D002452:Cell Count; D057225:Data Mining; D066264:Datasets as Topic; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000235:genetics; D007090:Image Interpretation, Computer-Assisted; D007091:Image Processing, Computer-Assisted; D008856:Microscopy, Fluorescence / Q000379:methods* / Q000592:standards; D009024:Morphogenesis; D009154:Mutation; D015027:Zebrafish / Q000235:genetics