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Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis


Although numerous fundamental aspects of development have been uncovered through the study of individual genes and proteins, system-level models are still missing for most developmental processes. The first two cell divisions of Caenorhabditis elegans embryogenesis constitute an ideal test bed for a system-level approach. Early embryogenesis, including processes such as cell division and establishment of cellular polarity, is readily amenable to large-scale functional analysis. A first step toward a system-level understanding is to provide ‘first-draft’ models both of the molecular assemblies involved1 and of the functional connections between them. Here we show that such models can be derived from an integrated gene/protein network generated from three different types of functional relationship2: protein interaction3, expression profiling similarity4 and phenotypic profiling similarity5, as estimated from detailed early embryonic RNA interference phenotypes systematically recorded for hundreds of early embryogenesis genes6. The topology of the integrated network suggests that C. elegans early embryogenesis is achieved through coordination of a limited set of molecular machines. We assessed the overall predictive value of such molecular machine models by dynamic localization of ten previously uncharacterized proteins within the living embryo.

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Figure 1: Integrated networks and phenotypic profiling.
Figure 2: Correlations between data sets (see also Supplementary Fig. S2).
Figure 3: Integrated network analysis.
Figure 4: Embryonic localization patterns of GFP-tagged fusion proteins analysed by time-lapse microscopy are largely consistent with model predictions.


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This work was supported by grants from NSF (to K.C.G. and D.S.G.), NIH/NHGRI (to M.V. and F.P.R.), NIH/NICHD (to F.P.) and Taplin Funds for Discovery (to F.P.R.). We thank members of our laboratories for discussions and comments on the manuscript.Author Contributions K.C.G., H.G., D.S.G., J.-D.J.H., T.H., N.B., N.L., J.H., G.F.B. and R.M. performed informatic analyses; A.J.S. and L.-S.C. performed cloning and localization experiments; K.C.G., F.P.R., M.V. and F.P. wrote the manuscript; B.S., C.E. and A.A.H. shared critical data before publication; and F.P.R., M.V. and F.P. provided guidance for experimental and informatic analyses and interpretation of results.

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Corresponding authors

Correspondence to Frederick P. Roth or Marc Vidal or Fabio Piano.

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Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Methods

This file contains a description of the methods used in the main text. (DOC 149 kb)

Supplementary Table S5

Analysis of shared GO functional annotations within EE networks, considering only gene pairs for which both members have some GO annotation. (DOC 34 kb)

Supplementary Table S6

Modular organization of the multiple support network. a, Summary of molecular machine models. b, Triple support network. c, Multiple support network. (d–q) Individual molecular models from the multiple support network: d, Ribosome; e, Proteasome; f, F1F0 ATPase; g, Vacuolar ATPase; h, Anaphase promoting complex (APC); i, Polarity; j, Actins; k, Microtubule (MT) cytoskeleton; l, Histones; m, Chromosome maintenance and nuclear membrane function; n, mRNA and protein metabolism; o, Translation initiation; p, COPI coatomer complex; q, Oocyte integrity and meiosis. (XLS 1094 kb)

Supplementary Data File S1

These two files contain the set of gene/protein interactions describing the entire integrated network for 661 EE genes based on a compendium of interactome, transcriptome, and phenome data, as presented in Figure 3a. As in the figure, links between genes/proteins with multiple degrees of support have been merged into single edges for visual clarity. These data are provided in Cytoscape format ( This file is a Cytoscape simple interaction file (SIF) containing pairwise interactions. “pp”, protein interaction; “pc”, phenocorrelation; “ec”, expression correlation. Multiple support edges are indicated by combinations of these three abbreviations (“pppc”, “pcec”, “ppec”, and “pppcec”). (SIF 618 kb)

Supplementary Data File 2

Cytoscape node attribute (NOA) file translating cosmid names to 3-letter gene names. (NOA 10 kb)

Supplementary Movie S1

These ten movie files are time-lapse movies of all localization studies of expressed protein-GFP fusions in the early C. elegans embryo. This movie shows GFP–T26A5.8 localization in C. elegans during early embryogenesis. The localization is intensely nuclear at interphase and weakly chromosomal at metaphase, with some cytoplasmic punta. Time stamp, in minutes, is shown. (MOV 4152 kb)

Supplementary Movie S2

This movie shows GFP–F35B12.5 localization in C. elegans during early embryogenesis. The localization appears centriolar and transiently on the spindle. Time stamp, in minutes, is shown. (MOV 882 kb)

Supplementary Movie S3

This movie shows GFP–Y45F10D.9 localization in C. elegans during early embryogenesis. The localization appears centriolar and transiently on the spindle. Time stamp, in minutes, is shown. (MOV 4255 kb)

Supplementary Movie S4

This movie shows GFP–W08F4.8 localization in C. elegans during early embryogenesis. There is a nuclear “flash” at mitosis and nuclear exclusion at interphase. Time stamp, in minutes, is shown. (MOV 3543 kb)

Supplementary Movie S5

dThis movie shows GFP–C38D4.3 localization in C. elegans during early embryogenesis. The signal is diffused in the nucleus and enriched on the nuclear periphery at telophase to the next mitosis, when chromosomes form and are labelled in a way that eventually resemble kinetochore enrichment. Time stamp, in minutes, is shown. (MOV 5657 kb)

Supplementary Movie S6

This movie shows GFP–T24F1.2 localization in C. elegans during early embryogenesis. Nuclear envelope enrichment. Time stamp, in minutes, is shown. (MOV 2835 kb)

Supplementary Figure S1a

Phenoclustering of 661 genes required for early embryogenesis. A global view with numbered clusters and enriched GO annotations labelled, and highlighting clusters containing proteins tested by localization. (PDF 2669 kb)

Supplementary Movie S7

This movie shows GFP–C29E4.2 localization in C. elegans during early embryogenesis. Condensing chromosomes are labeled. Time stamp, in minutes, is shown. (MOV 1079 kb)

Supplementary Movie S8

This movie shows GFP–Y55B1BR.3 localization in C. elegans during early embryogenesis. Diffused nuclear localization during interphase and not visible in nucleus at mitosis. Time stamp, in minutes, is shown. (MOV 9512 kb)

Supplementary Movie S9

This movie shows GFP–F55C5.4 localization in C. elegans during early embryogenesis. Localization on condensing chromosomes is visible with a typical kinetochore pattern. Time stamp, in minutes, is shown. (MOV 5438 kb)

Supplementary Movie S10

This movie shows GFP–T10B5.6 localization in C. elegans during early embryogenesis. Localization on condensing chromosomes is visible with a typical kinetochore pattern. Time stamp, in minutes, is shown. (MOV 2762 kb)

Supplementary Figure S1b

An expanded view showing all gene names. (PDF 5575 kb)

Supplementary Figure S2

Global correlations between interactome, transcriptome, and phenome data for the EE dataset, excluding ribosomal and proteasomal genes. (PDF 772 kb)

Supplementary Figure Legends

dLegends for Supplementary Figures S1 and S2. (DOC 25 kb)

Supplementary Table S1

‘Fly-to-worm’ interologues for high-confidence D. melanogaster Y2H interactions from Giot et al., 2003. Joint e-values and percent identities over the lengths of the query and target proteins are indicated. See Supplementary Methods for details. (XLS 154 kb)

Supplementary Table S2

Functional characteristics (Gene Ontology (GO) terms) enriched in phenoclusters from Fig. 1b and Supplementary Fig. S1. (XLS 30 kb)

Supplementary Table S3

Comparison of EE 'within-set' network versus random within-set networks from WI7 (see Supplementary Methods for selection of random gene sets from WI7). (XLS 37 kb)

Supplementary Table S4

Analysis of shared GO functional annotations within EE networks. (DOC 44 kb)

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Gunsalus, K., Ge, H., Schetter, A. et al. Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis. Nature 436, 861–865 (2005).

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