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A gene regulatory network controlling the embryonic specification of endoderm


Specification of endoderm is the prerequisite for gut formation in the embryogenesis of bilaterian organisms. Modern lineage labelling studies1,2,3 have shown that in the sea urchin embryo model system, descendants of the veg1 and veg2 cell lineages produce the endoderm, and that the veg2 lineage also gives rise to mesodermal cell types. It is known that Wnt/β-catenin signalling is required for endoderm specification4,5,6 and Delta/Notch signalling is required for mesoderm specification7,8,9. Some direct cis-regulatory targets of these signals have been found10,11 and various phenomenological patterns of gene expression have been observed in the pre-gastrular endomesoderm. However, no comprehensive, causal explanation of endoderm specification has been conceived for sea urchins, nor for any other deuterostome. Here we propose a model, on the basis of the underlying genomic control system, that provides such an explanation, built at several levels of biological organization. The hardwired core of the control system consists of the cis-regulatory apparatus of endodermal regulatory genes, which determine the relationship between the inputs to which these genes are exposed and their outputs. The architecture of the network circuitry controlling the dynamic process of endoderm specification then explains, at the system level, a sequence of developmental logic operations, which generate the biological process. The control system initiates non-interacting endodermal and mesodermal gene regulatory networks in veg2-derived cells and extinguishes the endodermal gene regulatory network in mesodermal precursors. It also generates a cross-regulatory network that specifies future anterior endoderm in veg2 descendants and institutes a distinct network specifying posterior endoderm in veg1-derived cells. The network model provides an explanatory framework that relates endoderm specification to the genomic regulatory code.

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Figure 1: Endodermal gene expression and perturbation matrix.
Figure 2: Separation of endoderm and mesoderm regulatory states.
Figure 3: Separation of anterior and posterior endoderm regulatory states.
Figure 4: Anterior and posterior GRNs just before gastrulation.

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We acknowledge technical assistance from J. Yun, who executed much of the perturbation analysis matrix, and from A. Puszynska and E. Erkenbrack, who contributed to whole-mount in situ hybridization results. We are grateful to E. Rothenberg for a detailed critique of the manuscript. I.S.P. was the recipient of a fellowship from the Swiss National Science Foundation in the initial stages of this work. The research was supported by National Institutes of Health grant HD37105 to E.H.D.

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This research was conceived by I.S.P. and E.H.D. and all experiments were designed and executed by I.S.P. with the assistance acknowledged above. The results were interpreted by I.S.P. and E.H.D., who also contributed jointly to the manuscript.

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Correspondence to Isabelle S. Peter or Eric H. Davidson.

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The authors declare no competing financial interests.

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Peter, I., Davidson, E. A gene regulatory network controlling the embryonic specification of endoderm. Nature 474, 635–639 (2011).

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