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Experimentally based sea urchin gene regulatory network and the causal explanation of developmental phenomenology

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Abstract Gene regulatory networks (GRNs) for development underlie cell fate specification and differentiation. Network topology, logic, and dynamics can be obtained by thorough experimental analysis. Our understanding of the GRN controlling endomesoderm specification in the sea urchin embryo has attained an advanced level such that it explains developmental phenomenology. Here we review how the network explains the mechanisms utilized in development to control the formation of dynamic expression patterns of transcription factors and signaling molecules. The network represents the genomic program controlling timely activation of specification and differentiation genes in the correct embryonic lineages. It can also be used to study evolution of body plans. We demonstrate how comparing the sea urchin GRN to that of the sea star and to that of later developmental stages in the sea urchin, reveals mechanisms underlying the origin of evolutionary novelty. The experimentally based GRN for endomesoderm specification in the sea urchin embryo provides unique insights into the system level properties of cell fate specification and its evolution. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Physiology > Physiology of Model Organisms

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Flow chart of the experimental analysis that was conducted to construct the gene regulatory network controlling endomesoderm specification in sea urchin embryo. The transcription factors of the sea urchin were identified computationally using the sea urchin genome.12–17 The expression patterns and time courses of all the identified transcription factors were measured by whole mount in situ hybridization (WMISH) and quantitative polymerase chain reaction (QPCR) respectively. The expression patterns provided the identification of the players and their order and place of appearance. The functional regulatory connections between the active regulatory genes were then obtained by a perturbation analysis, where every regulatory gene in the network was perturbed, and the effect on every other gene in the network was assessed by QPCR and WMISH.6 For key regulatory genes the perturbation analysis was followed by cis‐regulatory analysis, the precise identification and characterization of the cis‐acting genomic sequences regulating the transcription of a gene.5 Cis‐regulatory analysis reveals which regulatory connection is direct and what is the logic function that a cis‐regulatory module executes on its direct inputs. The network topology, the response functions of the cis‐regulatory modules, and the spatiotemporal expression patterns of the network genes were then incorporated into a comprehensive model. This linear diagram is of course a simplification of the actual research process which goes back and forth to improve our understanding in the light of new findings.

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Gene regulatory network (GRN) evolution underlies the evolution of body plans. (a) Sea urchin larva at 72 hpf (Strongylocentrotus purpuratus, reprinted from Ref 34). (b) Sea star larva at 70 hpf (Asterina miniata, reprinted from Ref 35). (c) Endomesoderm circuits controlling the specification of the sea urchin skeleton, pigment cells, blastocoelar cells and endoderm. (d) Endomesoderm circuits controlling the specification of sea star blastocoelar cells and endoderm. (e) The mechanism of network rewiring—comparing the cis‐regulatory modules of the otx gene in sea star and sea urchin reveals the change and conservation of the genomic code (Reprinted with permission from Ref 22. Copyright 2007 Elsevier).

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The skeletonic lineage specification and differentiation. (a) Partial gene regulatory network of some of the skeletonic genes, including the double negative gate of Pmar1 and HesC and a cascade of feed‐forward loops constructed by the transcription factors Ets1, Alx1, and Dri, and the differentiation gene cyclophilin. (b) Expression pattern of Pmar1, HesC, Ets1, and Alx1 at 8 hpf. (c) Expression pattern of Ets1, Alx1, Dri, and Cyclophilin at 12 hpf. D. Time courses of the mRNA level of the genes pmar1, ets1, alx1, dri and cyclophilin measured by quantitative polymerase chain reaction (QPCR). (Data obtained from Ref 7, Supplementary Material).

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Genomic code of the dynamic expression pattern of signaling pathways. (a) Schematic diagrams of the sea urchin (Strongylocentrotus purpuratus) embryo development. Red cells at 7 hpf are the large micromeres, from their descendants the skeleton forms. The blue‐purple tier of cells at 7 h is the macromeres. Their descendants form mesoderm (purple) and endoderm (blue) cells. (b) The circuit components active in the skeletogenic mesenchymes (SMs) and nonskeletogenic mesoderms (NSMs) until eighth cleavage (right). Diagrams of the expression pattern of the Wnt8 and Delta ligands at these stages (left). (c) The circuit components active in the NSM and endoderm at early mesenchyme blastula (right). Diagrams of the Wnt8 and Delta expression pattern at this time (left).

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