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Biology
Systems Biology

A genomic regulatory network for development

Profile image of gabriele amoregabriele amore

2002, Science

Abstract
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The paper presents a comprehensive genomic regulatory network that outlines the development of the body plan in organisms, specifically focusing on the specification of endoderm and mesoderm in sea urchin embryos. Drawing from a blend of large-scale perturbation analyses, genomic data, and computational methodologies, the research identifies over 40 genes involved in this process, highlighting their interconnected roles. The architecture of this network illuminates both specific and generalized mechanisms of developmental biology, emphasizing how cellular identities are determined progressively throughout embryonic development.

Figures (7)
Table 1. Phenomenological aspects of endomesoderm specification in sea urchin embryos: developmental process (55.
Table 1. Phenomenological aspects of endomesoderm specification in sea urchin embryos: developmental process (55.
In itself, perturbation analysis cannot dis- tinguish between direct and indirect effects: Blockade of the expression of a gene that encodes a transcriptional activator may de- crease expression of both immediately and secondarily downstream target genes; and if it encodes a repressor, blockade of its expres- sion may increase expression of both. Direct effects are those in which a perturbation in the expression or function of a transcription factor causes changes in the expression of another gene, because target sites for that factor are included in a cis-regulatory ele- ment of the gene. cis-Regulatory analysis can therefore be used to resolve whether effects on a given control element are indeed direct. Another approach that we have used at sev- In an iterative process, the inferences from the experimental perturbation results were checked against the network model, further ex- periments were designed, the model was altered according to their results if necessary, and so A major gene discovery effort was undertak- en in order to clothe with real genes the arma- ture of interactions implied by the embryology, and to add to the collection of genes already known to be involved in endomesoderm speci- fication. Several screens were carried out (Table 2) in which endomesoderm specification was perturbed so as to generate material for use with a very sensitive subtractive hybridization tech- nology designed for use with large-scale arrays of ~10° clone cDNA libraries (macroarrays) (35). The purpose was to create probes in which sequences differentially expressed in the endo- tion. A 48-hour control embryo is shown laterally, witn the oral side on the left; and ar embryo of the same age expressing an injected mRNA that encodes the intracellular domain of cadherin is shown on the right (image from A Ransick). The cadherin embryo consists of a hollow ball of ectoderm; endomesodermal specification has been completely wiped out. (D) Effec of the introduction of a negatively acting derivative of the N receptor. A control 37-hour late gastrula is shown on the left, and on the righ is an embryo of the same age expressing an injected mRNA encoding the extracellular domain of the N receptor (negN) (image from C Calestani). This embryo has a normal complement of skeletogenic mesenchyme cells and a well-formed gut but only a very few mesoderma cells of veg, origin as compared with the control.
In itself, perturbation analysis cannot dis- tinguish between direct and indirect effects: Blockade of the expression of a gene that encodes a transcriptional activator may de- crease expression of both immediately and secondarily downstream target genes; and if it encodes a repressor, blockade of its expres- sion may increase expression of both. Direct effects are those in which a perturbation in the expression or function of a transcription factor causes changes in the expression of another gene, because target sites for that factor are included in a cis-regulatory ele- ment of the gene. cis-Regulatory analysis can therefore be used to resolve whether effects on a given control element are indeed direct. Another approach that we have used at sev- In an iterative process, the inferences from the experimental perturbation results were checked against the network model, further ex- periments were designed, the model was altered according to their results if necessary, and so A major gene discovery effort was undertak- en in order to clothe with real genes the arma- ture of interactions implied by the embryology, and to add to the collection of genes already known to be involved in endomesoderm speci- fication. Several screens were carried out (Table 2) in which endomesoderm specification was perturbed so as to generate material for use with a very sensitive subtractive hybridization tech- nology designed for use with large-scale arrays of ~10° clone cDNA libraries (macroarrays) (35). The purpose was to create probes in which sequences differentially expressed in the endo- tion. A 48-hour control embryo is shown laterally, witn the oral side on the left; and ar embryo of the same age expressing an injected mRNA that encodes the intracellular domain of cadherin is shown on the right (image from A Ransick). The cadherin embryo consists of a hollow ball of ectoderm; endomesodermal specification has been completely wiped out. (D) Effec of the introduction of a negatively acting derivative of the N receptor. A control 37-hour late gastrula is shown on the left, and on the righ is an embryo of the same age expressing an injected mRNA encoding the extracellular domain of the N receptor (negN) (image from C Calestani). This embryo has a normal complement of skeletogenic mesenchyme cells and a well-formed gut but only a very few mesoderma cells of veg, origin as compared with the control.
*Cad, intracellular domain of cadherin (Fig. 2C). This domain sequesters -catenin, which is thereby localized at the inner surface of the cell membrane. An excess of the cadherin intracellular domain severely decreases the availability of B-catenin for transit into the nucleus. tLiCl-treated embryos produce excess endomesoderm (12, 62). {The extracellular domain of N acts as a repressor of N function in mesoderm specification (27) ( Fig. 2D). §The brachyury (bra) gene is active by about 18 hours. Driver mRNA was extracted from normal 15-hour embryos. Ectopic bra-expressing cells were obtained by disaggregating 18-hour embryos expressing genetic constructs that produce bra mRNA under the control of a ubiquitously active cis-regulatory element. The transgenic cells were tagged with green fluorescent protein (GFP) and isolated by fluorescence-activated cell sorting (FACS) (37). MASO embryos were collected at 24 to 27 hours (late blastula stage). #Cells expressing bra were obtained by FACS as above, but at 24 to 27 hours (37). Table 2. Differential gene discovery screens. Macroarray filter screens were carried out with probes prepared by high- -C,T subtractive hybridization, using single-stranded driver and selectate, as described (35). "Selectate” denotes the cDNA preparation that contains the sequences of interest, in contrast to the nucleic acid present in excess in the hybridization reaction: The “Driver,” which lacks these sequences. In the subtractive hybridizations, the reactions were carried out to near termination with respect to driver, and nonhybridized selectate sequences were recovered by hydroxyapatite chromatography (35).
*Cad, intracellular domain of cadherin (Fig. 2C). This domain sequesters -catenin, which is thereby localized at the inner surface of the cell membrane. An excess of the cadherin intracellular domain severely decreases the availability of B-catenin for transit into the nucleus. tLiCl-treated embryos produce excess endomesoderm (12, 62). {The extracellular domain of N acts as a repressor of N function in mesoderm specification (27) ( Fig. 2D). §The brachyury (bra) gene is active by about 18 hours. Driver mRNA was extracted from normal 15-hour embryos. Ectopic bra-expressing cells were obtained by disaggregating 18-hour embryos expressing genetic constructs that produce bra mRNA under the control of a ubiquitously active cis-regulatory element. The transgenic cells were tagged with green fluorescent protein (GFP) and isolated by fluorescence-activated cell sorting (FACS) (37). MASO embryos were collected at 24 to 27 hours (late blastula stage). #Cells expressing bra were obtained by FACS as above, but at 24 to 27 hours (37). Table 2. Differential gene discovery screens. Macroarray filter screens were carried out with probes prepared by high- -C,T subtractive hybridization, using single-stranded driver and selectate, as described (35). "Selectate” denotes the cDNA preparation that contains the sequences of interest, in contrast to the nucleic acid present in excess in the hybridization reaction: The “Driver,” which lacks these sequences. In the subtractive hybridizations, the reactions were carried out to near termination with respect to driver, and nonhybridized selectate sequences were recovered by hydroxyapatite chromatography (35).
Fig. 3. Regulatory gene network for endomesoderm specification: the view from the genome. The current version of the model in this figure and the perturbation data on which it is based are available on a Web site (30); for additional details and discussion, see (79). At the top, above the triple line, are the earliest interactions; in the middle tier, the spatial domains are color-coded (Fig. 1), and genes are placed therein according to their final loci of expression. As indicated (black background labels), the lavender area at the left represents the skeletogenic micromere (mic) domain before ingression; the light green area indicates the veg, endo- mesoderm domain, with genes eventually expressed in endoderm on yellow backgrounds and genes eventually expressed in mesoderm on blue backgrounds; the tan box at right represents the veg, endoderm domain. Many genes are initially expressed over broader ranges, and their expression later resolves to the definitive domains. The rectangles in the lower tier of the diagram show downstream differentiation genes (PMC, “primary” or skeletogenic mesenchyme). Short horizontal lines from which bent arrows extend represent cis-regulatory elements responsible for expression of the genes named beneath the line. Embryonic gene expression was perturbed in specific ways as in Fig. 2. The arrows and barred lines indicate the inferred normal function of the input (activation or repression), as deduced from changes in transcript levels due to the perturbations. Each input arrow constitutes a prediction of specific transcription factor target site sequence(s) in the cis-regulatory control element. In some cases, the predicted target sites have been identified in experimentally defined cis-regulatory elements that generate the correct spatial pattern of expression (solid triangles). At the upper left, the light blue arrow represents the maternal B-catenin (cB) nuclearization system (x). This transcriptional system (n8—TCF) is soon accelerated and then taken over by zygotic Wnt8 (dark blue lines); its initial activation, of mixed zygotic and maternal origins, is shown in light blue. Data for the roles of SoxB1 and Krippel-like (Krl) are from (50, 57). Data for the role of Ets are from (52, 65). “Micr/Nuc Mat Otx” refers to the early localization of maternal Otx in micromere nuclei at fourth cleavage (56). Genes labeled “Repressor” are inferred; all other genes shown are being studied at the DNA sequence level and by multiplexed QPCR. “Ub” indicates a ubiquitously active positive input inferred on the basis of ubiquitous expression seen by whole-mount in situ hybridization, under conditions in which a spatial repression system that normally confines expression has been disarmed. Dotted lines in the diagram indicate inferred but indirect relationships. Arrows inserted in arrow tails indicate intercellular signaling interactions. Small open or closed circles indicate perturbation effects that resist rescue by the introduction of mRNA where there is a possibility that the effect seen is actually an indirect result of an upstream interaction; that is, this possibility of such an indirect effect has been experimentally excluded, and both sites are shown as probable direct inputs (79). Large open ovals represent cyto- plasmic biochemical interactions at the protein level, such as those responsible for nuclearization of B-catenin, for the effect of Delta on N (66); or for the effect of Neuralized, an E3 ubiquitin ligase with specificity for Delta (67, 68). The network explains some of the pheno- types observed when given processes are per- turbed, in terms of its consequential regulatory logic. For example, as shown in Fig. 2C, if B-catenin nuclearization is prevented by intro- duction of mRNA encoding the intracellular domain of cadherin, neither endodermal nor me- sodermal cell types and structures appear. In default of B-catenin/Tcf inputs, the embryo be- comes a hollow ball of ectoderm. Note, howev- er, that all the perturbation data underlying the network in Fig. 3 were obtained between 6 and 24 hours, long before any gastrulation pheno- types can be seen (30). Initiation of B-catenin nuclearization produces such a catastrophic re-
Fig. 3. Regulatory gene network for endomesoderm specification: the view from the genome. The current version of the model in this figure and the perturbation data on which it is based are available on a Web site (30); for additional details and discussion, see (79). At the top, above the triple line, are the earliest interactions; in the middle tier, the spatial domains are color-coded (Fig. 1), and genes are placed therein according to their final loci of expression. As indicated (black background labels), the lavender area at the left represents the skeletogenic micromere (mic) domain before ingression; the light green area indicates the veg, endo- mesoderm domain, with genes eventually expressed in endoderm on yellow backgrounds and genes eventually expressed in mesoderm on blue backgrounds; the tan box at right represents the veg, endoderm domain. Many genes are initially expressed over broader ranges, and their expression later resolves to the definitive domains. The rectangles in the lower tier of the diagram show downstream differentiation genes (PMC, “primary” or skeletogenic mesenchyme). Short horizontal lines from which bent arrows extend represent cis-regulatory elements responsible for expression of the genes named beneath the line. Embryonic gene expression was perturbed in specific ways as in Fig. 2. The arrows and barred lines indicate the inferred normal function of the input (activation or repression), as deduced from changes in transcript levels due to the perturbations. Each input arrow constitutes a prediction of specific transcription factor target site sequence(s) in the cis-regulatory control element. In some cases, the predicted target sites have been identified in experimentally defined cis-regulatory elements that generate the correct spatial pattern of expression (solid triangles). At the upper left, the light blue arrow represents the maternal B-catenin (cB) nuclearization system (x). This transcriptional system (n8—TCF) is soon accelerated and then taken over by zygotic Wnt8 (dark blue lines); its initial activation, of mixed zygotic and maternal origins, is shown in light blue. Data for the roles of SoxB1 and Krippel-like (Krl) are from (50, 57). Data for the role of Ets are from (52, 65). “Micr/Nuc Mat Otx” refers to the early localization of maternal Otx in micromere nuclei at fourth cleavage (56). Genes labeled “Repressor” are inferred; all other genes shown are being studied at the DNA sequence level and by multiplexed QPCR. “Ub” indicates a ubiquitously active positive input inferred on the basis of ubiquitous expression seen by whole-mount in situ hybridization, under conditions in which a spatial repression system that normally confines expression has been disarmed. Dotted lines in the diagram indicate inferred but indirect relationships. Arrows inserted in arrow tails indicate intercellular signaling interactions. Small open or closed circles indicate perturbation effects that resist rescue by the introduction of mRNA where there is a possibility that the effect seen is actually an indirect result of an upstream interaction; that is, this possibility of such an indirect effect has been experimentally excluded, and both sites are shown as probable direct inputs (79). Large open ovals represent cyto- plasmic biochemical interactions at the protein level, such as those responsible for nuclearization of B-catenin, for the effect of Delta on N (66); or for the effect of Neuralized, an E3 ubiquitin ligase with specificity for Delta (67, 68). The network explains some of the pheno- types observed when given processes are per- turbed, in terms of its consequential regulatory logic. For example, as shown in Fig. 2C, if B-catenin nuclearization is prevented by intro- duction of mRNA encoding the intracellular domain of cadherin, neither endodermal nor me- sodermal cell types and structures appear. In default of B-catenin/Tcf inputs, the embryo be- comes a hollow ball of ectoderm. Note, howev- er, that all the perturbation data underlying the network in Fig. 3 were obtained between 6 and 24 hours, long before any gastrulation pheno- types can be seen (30). Initiation of B-catenin nuclearization produces such a catastrophic re-
sult because multiple endodermal and meso- derm regulatory genes depend on a B-catenin/ Tcf input. For these genes, only a few percent of control transcript levels survive cadherin mRNA injection (/9, 30). Another interesting phenotype is obtained when embryos are treated with a-gcm MASO. The result is albino larvae (49). The gene gcm is ultimately expressed in pigment cells (36), and a downstream target of gcm is the pks (polyketide synthase) gene, which is also expressed in pigment cells (38, 39). This product (and other pigment cell genes under gcm control, not shown) is likely to be required for synthesis of the red quinone pigment these cells produce. Upstream, the network shows gcm to be a target of the N signaling system, because its expression is severely depressed by the introduction of a negatively acting N deriv- ative (19) (Fig. 2D). In fact, gem expression begins in the single ring of mesoderm progenitor cells that directly receives the Delta micromere signal (36). So we now have a sequence of DNA-based interactions that leads from the ini- tial specification to the terminal differentiation of pigment cells and that explains the albino phenotype. Similarly, the network explains the The view from the genome provides a qual- itative DNA-level explanation for the spatial domains of expression of many endomesoder- mal regulatory genes. No two of these genes have identical inputs: Each cis-regulatory infor- mation processing system has its own job to do. The initial events in endomesoderm specifi- cation occur in the micromeres and in the veg, must normally act as a repressor. (E) Expression of sm50, a skeleto- genic differentiation gene exclusively in skeletogenic mesenchyme cells (69). (F) Global expression of sm50 in embryos expressing pmar1 globally. (G) Expression of the skeletogenic regulator tbr in embryos expressing pmar7 mRNA globally. (F) and (G) show that the whole embryo has been converted to a state of skeletogenic mesenchyme differentiation. Note the rounded form of the cells at 24 hours in (F) as compared to the control in (E), due to their tendency to behave mesenchymally.
sult because multiple endodermal and meso- derm regulatory genes depend on a B-catenin/ Tcf input. For these genes, only a few percent of control transcript levels survive cadherin mRNA injection (/9, 30). Another interesting phenotype is obtained when embryos are treated with a-gcm MASO. The result is albino larvae (49). The gene gcm is ultimately expressed in pigment cells (36), and a downstream target of gcm is the pks (polyketide synthase) gene, which is also expressed in pigment cells (38, 39). This product (and other pigment cell genes under gcm control, not shown) is likely to be required for synthesis of the red quinone pigment these cells produce. Upstream, the network shows gcm to be a target of the N signaling system, because its expression is severely depressed by the introduction of a negatively acting N deriv- ative (19) (Fig. 2D). In fact, gem expression begins in the single ring of mesoderm progenitor cells that directly receives the Delta micromere signal (36). So we now have a sequence of DNA-based interactions that leads from the ini- tial specification to the terminal differentiation of pigment cells and that explains the albino phenotype. Similarly, the network explains the The view from the genome provides a qual- itative DNA-level explanation for the spatial domains of expression of many endomesoder- mal regulatory genes. No two of these genes have identical inputs: Each cis-regulatory infor- mation processing system has its own job to do. The initial events in endomesoderm specifi- cation occur in the micromeres and in the veg, must normally act as a repressor. (E) Expression of sm50, a skeleto- genic differentiation gene exclusively in skeletogenic mesenchyme cells (69). (F) Global expression of sm50 in embryos expressing pmar1 globally. (G) Expression of the skeletogenic regulator tbr in embryos expressing pmar7 mRNA globally. (F) and (G) show that the whole embryo has been converted to a state of skeletogenic mesenchyme differentiation. Note the rounded form of the cells at 24 hours in (F) as compared to the control in (E), due to their tendency to behave mesenchymally.
The system next proceeds to stabilize positively, and to expand, the endomeso- dermal regulatory state (Fig. 5A, red inter- actions). The result is essentially to lock the process into forward drive: “commitment,” here seen to be hardwired into the regula- tory circuitry. The Wnt8/Tcf loop discussed above is a piece of this process, which consists mainly of positive cis-regulatory feedbacks; that is, auto- and cross-regula- ig. 5. Lock-down functions and expression of the complete regulatory state. (A) Institution of egulatory lock-down devices, shown in color. This view from the endomesoderm nuclei extends rom about sixth cleavage to midblastula stage (Fig. 1). The features illuminated are the zygotic Vnt8/Tcf loop (hatched blue), and zygotic auto- and cross-regulations (red), as discussed in text he N signal transduction input into the gcm gene is shown in hatched orange. (B) Complete ctivation of the endomesodermal regulatory system: the view from the nuclei from midblastule o after mesenchyme blastula (Fig. 1). By this point, both endoderm and mesoderm specifications ave become final, and all genes shown are being expressed. All can be accounted for in terms ot he set of inputs included in the color key at the bottom. Except for the Delta and Wnté ignal-mediated inputs, which are transient, these regulatory inputs have by now achievec tabilization by the interactions shown in (A).
The system next proceeds to stabilize positively, and to expand, the endomeso- dermal regulatory state (Fig. 5A, red inter- actions). The result is essentially to lock the process into forward drive: “commitment,” here seen to be hardwired into the regula- tory circuitry. The Wnt8/Tcf loop discussed above is a piece of this process, which consists mainly of positive cis-regulatory feedbacks; that is, auto- and cross-regula- ig. 5. Lock-down functions and expression of the complete regulatory state. (A) Institution of egulatory lock-down devices, shown in color. This view from the endomesoderm nuclei extends rom about sixth cleavage to midblastula stage (Fig. 1). The features illuminated are the zygotic Vnt8/Tcf loop (hatched blue), and zygotic auto- and cross-regulations (red), as discussed in text he N signal transduction input into the gcm gene is shown in hatched orange. (B) Complete ctivation of the endomesodermal regulatory system: the view from the nuclei from midblastule o after mesenchyme blastula (Fig. 1). By this point, both endoderm and mesoderm specifications ave become final, and all genes shown are being expressed. All can be accounted for in terms ot he set of inputs included in the color key at the bottom. Except for the Delta and Wnté ignal-mediated inputs, which are transient, these regulatory inputs have by now achievec tabilization by the interactions shown in (A).

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  1. References and Notes
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