The Regulatory Genome: Gene Regulatory Networks In Development And Evolution

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The Regulatory Genome offers evo-devo aficionados an intellectual masterpiece to praise or to pan but impossible to ignore. Although there is clearly still much to learn about the evolution of gene networks and how these in turn constrain evolution, Davidson has placed a cornerstone for the comparative analysis of gene regulatory networks.

Gene regulatory networks for development

Further research in this rather fresh field promises to help delineate the links between development and evolution. I recommend it highly to anyone interested in the subject. Davidson does an excellent job of reducing the complexity of different developmental pathways and modes of embryonic development in diverse animal phyla to a set of simplified and logical concepts and principles. He provides excellent illustrations and experimental examples derived from several model organisms: What is especially attractive about the book are the regulatory networks drawn as simple wiring and computational diagrams.

These go a long way towards explaining the basic regulatory logic and engineering principles of some of the most complex biological phenomena: This book should be read by all biologists who want to understand how development and evolution take place and what governs the workings of genomes. I also recommend it to computer scientists and engineers who are interested in the budding field of computational biology, as reading it does not require an extensive background in developmental biology.

I strongly recommend this book to young scientists with multidisciplinary talents, who will advance the authors idea of the regulatory genome into its next phase, a voyage into the sea of genome complexity This is a milestone work that needs to be read by every biologist interested in development, evolution and a systems view of life for it provides deep insights into each of these areas. View other products from the same publisher.

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C The cis-regulatory programming responsible for reception by adjacent presumptive mesodermal cells of a Delta signal emitted by skeletogenic cells and for activation of pigment cell differentiation genes 29 ; these are SuTx Sulfotransferase , Dpt Dopachrome tautomerase , Pks Polyketide synthetase , and FvMo Flavine-containing monoxigenase. The Delta signal is received by a Notch receptor that together with a Supressor of Hairless [Su H ] transcription factor already present in these cells transmits a permissive input to the cis-regulatory module of the gcm regulatory gene.

These relationships were established experimentally in gene transfer studies by using a mutant Su H factor and by mutational analysis of the gcm cis-regulatory module A. After activation, gcm locks itself on by autoregulation. D Endoderm specification feedback loop. The network consists of almost 50 genes. The large pastel areas in Fig. The tan area on the right represents a late-specified endodermal region that invaginates at the end of gastrulation and produces posterior portions of the gut. In all these areas, most of the named genes encode transcription factors; the remainder are differentially expressed signaling components.

At the bottom of the diagram, the smaller rectangles enclose samples of the respective sets of differentiation genes, i. The network image shows the transcription factor inputs vertical arrows and barred lines that impinge on the relevant cis-regulatory modules, which are symbolized by the short horizontal lines overlying the names of the respective genes. From each gene the color-coded thin lines display the outputs to other genes in the network the mode of presentation and its significance are discussed in refs.

Evidence on which the network is based includes the temporal expression of all of the genes in the network obtained by quantitative PCR ; spatial expression of these genes obtained by whole-mount in situ hybridization ; and the results of a large-scale perturbation analysis, in which expression of each gene was taken out of the system usually by use of antisense morpholino-substituted oligonucleotides , and the effects on all other relevant genes were measured by quantitative PCR.

However, for other essential supporting information , where the causal evidence is too unique to be easily tabularized, specific publications must be consulted also listed on the web site. For example, such evidence includes the effects of ectopic expression of given regulatory genes on spatial specification events e.

Completeness is the fraction of regulatory genes actually involved in the process that is included explicitly in the network as shown. Completeness can be addressed only with the aid of genomic sequence information, which provides the possibility of computational screens and the possibility of reference to the complete regulatory gene repertoire.

Authenticity is the level at which the interactions pictured in the network have been demonstrated to represent cis-regulatory transactions encoded in the genomic sequence. We argue that there is only one way to authenticate a GRN, and that is by means of direct experimental manipulation of individual cis-regulatory modules. Much of the architecture of the sea urchin network in Fig. Thus, with respect to authentication, these networks are among the standards in this young field.

With regard to the GRN in Fig. However, because the genome sequence of Strongylocentrotus purpuratus is now becoming available obtained by the Human Genome Sequence Center of Baylor University; National Center for Biotechnology Information Trace Repository , we have been able to determine the temporal and spatial expression of hundreds of predicted regulatory genes. It has turned out that the number of new genes that are specifically expressed in early endomesodermal domains of the embryo can be counted on the fingers of one hand for each territory.

Thus, indications are that the current version of the network is not very incomplete, although we are aware of several places where linkages and gene targets are missing and of several spatial patterns of expression that are not yet completely explained. A large-scale effort has been mounted with respect to authentication of the endomesoderm network, as indicated by the thin red circles in Fig. For every one of the circled genes, a small several hundred base pairs DNA fragment has been recovered that, when associated with a reporter gene and introduced into sea urchin eggs, reproduces the developmental pattern of expression of the endogenous gene.

The circled genes include most of the key nodes of the network.

Just the fact that all of the predicted cis-regulatory modules in the circles have been experimentally demonstrated to exist provides the basic level of authentication: The next level of analysis is to determine whether each cis-regulatory module responds in the same way as the associated gene in the living embryo when challenged by experimental perturbations. The final level is to show by mutation that the module contains the target site s for the inputs predicted in the network or, if not, to correct the network architecture.

Different cis-regulatory modules circled in Fig.

But for some modules, the analysis is complete, e. Where the evidence is in, the predictions of the network shown in Fig. There are three ways in which the GRN provides a qualitatively different and innovative kind of understanding not otherwise accessible. First, it explains, in the causal terms of the explicit genomic regulatory code, much of the phenomenology of early embryogenesis discovered in the course of years of painstaking experimental embryology.

A glance at the network tells us why this is, what functions are executed, and how these functions are programmed in the relevant genomic cis-regulatory modules. The cis-regulatory module driving the wnt8 gene itself is among these target genes The explanation, in terms of the genomic regulatory code, is that the relevant delta cis-regulatory module 28 is controlled by the skeletogenic lineage regulatory system, which prevents expression of its participant genes i. Thereby we can account for the localization of the Delta signal. The network shows, furthermore, that in the recipient cells, the Notch receptor transcriptional complex directly activates a regulatory gene gcm that in turn locks itself stably on A.

The Regulatory Genome: Gene Regulatory Networks in Development and Evolution

Thereby the network at last closes the conceptual and evidential gap between the static genomic program for development and the dynamic progression of spatial regulatory states. The second way in which the GRN provides a different kind of insight is in respect to its own modular structure. It is composed of multigenic assemblages of components that work together to accomplish given regulatory tasks, of which Fig. A particularly interesting example is shown in Fig. After early inputs activate the endomesoderm krox gene, the Krox transcription factor activates the otx gene, the products of which provide positive inputs into other endoderm regulators, including the pleiotropic, endoderm-specific gatae gene.

The modular organization of the network is just becoming possible to perceive. But it is of potentially large importance for modeling its function, for reconstructing or redesigning it in the laboratory, and for understanding its evolution. Dorsal—ventral patterning is implemented by the graded distribution of a maternal transcription factor, Dorsal, and culminates in the differentiation of specialized tissues, including cardiac mesoderm, the ventral midline of the nerve cord, and the amnioserosa 9.

During a period of just 90 min, from syncytial stages to the onset of gastrulation, the dorsal—ventral axis is subdivided into three basic tissues: Dorsal regions of the mesoderm form cardiac tissues reviewed in ref. Ventral regions of the neurogenic ectoderm form the mesectoderm or ventral midline, which is essential for the patterning of the neurons that comprise the ventral nerve cord reviewed in ref.

Finally, the dorsal-most regions of the dorsal ectoderm form a contractile extraembryonic membrane called the amnioserosa, which is essential for the process of germband elongation after gastrulation The dorsal—ventral patterning network is composed of nearly 60 genes Fig. Twelve of the genes encode proteins that are active in the perivitelline matrix surrounding the plasma membrane of the oocyte. They are responsible for creating an activity gradient of the Spitz ligand on the surface of the unfertilized egg, with peak levels in ventral regions and lower levels in more dorsal regions After fertilization, Spitz interacts with the Toll receptor, which triggers an intracellular signaling cascade that releases the Dorsal transcription factor from the Cactus inhibitor in the cytoplasm reviewed in ref.

This regulated nuclear transport is restricted to ventral and lateral regions of the early embryo and is thought to mirror the extracellular gradient of the active Spitz ligand. The dorsal—ventral GRN in Drosophila.

The overall presentation is similar to that in Fig. The diagram represents regulatory inputs and outputs for 46 genes expressed in the early embryo, from 2 to 5 h after fertilization. During this 3-h window, the syncytial embryo undergoes cellularization, mesoderm invagination, and the rapid phase of germband elongation. The color coding, from bottom to top, represents the three primary embryonic tissues as follows: The light shading to the left of the diagram represents syncytial stages, between 2 and 3 h after fertilization.

The darker shading to the right represents cellularized embryos undergoing gastrulation. Dorsal—ventral patterning is initiated by the graded distribution of the Dorsal transcription factor. Peak levels of Dorsal enter nuclei in ventral bottom regions of the embryo, intermediate levels in lateral regions that form the ventral neurogenic ectoderm, and low levels in the dorsal neurogenic ectoderm. This Dorsal nuclear gradient is formed by the differential activation of the Toll signaling pathway 35 , which in turn depends on the localized transcription of pipe in ventral follicle cells of the egg chamber The pipe gene is probably repressed by EGF signaling, which is restricted to dorsal follicle cells because of the asymmetric position of the oocyte nucleus Localized transcription of pipe in ventral follicle cells leads to a serine protease cascade on the ventral surface of the growing oocyte ndl, gd, snk, and ea that cleaves an inactive precursor form of the Spatzle spz ligand The active ligand is thought to be deposited in a graded fashion along the ventral and lateral surface of the unfertilized egg.

After fertilization, the Spz gradient leads to the Dorsal nuclear gradient within the syncytial embryo. Twi is an activator that works in concert with Dorsal to activate sna expression in the mesoderm 9 , and there is evidence that Twi also helps activate htl and hbr Dorsal, Twi, and Sna regulate a large number of genes during the syncytial phases of dorsal—ventral patterning, including brk , vnd , rho , and vn , which are selectively activated in ventral regions of the neurogenic ectoderm Dorsal and Twi work in a synergistic fashion to activate these genes, whereas the Sna repressor excludes their expression from the ventral mesoderm.

Low levels of the Dorsal gradient activate short gastrulation sog and thisbe ths throughout the neurogenic ectoderm, in both dorsal and ventral regions 9 , Both genes encode secreted signaling molecules; Sog inhibits Dpp signaling 61 , whereas Ths is related to FGF8 and activates FGF signaling in the dorsal mesoderm during gastrulation see below.

Low levels of Dorsal also repress tolloid tld , zerknullt zen , and decapentaplegic dpp , which are required for the patterning of the dorsal ectoderm after cellularization 9. Definitive tissues begin to arise from each of the generic embryonic territories at the onset of gastrulation. The shading highlights the tinman tin and even-skipped eve genes, which gives rise to derivatives of the dorsal mesoderm such as visceral and cardiac muscles The shading in the central neurogenic ectoderm highlights a positive feedback system that is coordinated by the regulatory gene sim.

An unknown Notch signal emanating from the mesoderm induces sim expression in the ventral-most row of cells in the neurogenic ectoderm. Sim activates several components of the EGF signaling pathway, including rho , star , and spitz 47 — Rho and Star are required for the processing of the Spitz ligand 63 , which activates a ubiquitous EGF receptor egfr. Activation of EGF signaling leads to the induction of pointed p1 pnt expression, which activates orthodenticle otd in the ventral midline 51 , EGF signaling and pnt either directly or indirectly maintain the expression of several genes in the neurogenic ectoderm that were previously activated by Dorsal plus Twi, including ind and vnd , which encode regulatory proteins that pattern the future ventral nerve cord 53 , Sim also participates in the activation of slit sli , which encodes a signaling molecule required for the proper organization of the neurons that comprise the nerve cord Finally, the shading on top right highlights the differentiation of two derivatives of the dorsal ectoderm: A Dpp activity gradient is created in the dorsal ectoderm from the combined action of the Sog inhibitor emanating from the neurogenic ectoderm and the Tld protease, which releases Dpp from Sog at the dorsal midline Dpp works together with a ubiquitous bone morphogenetic protein BMP signaling molecule called Screw Scw.

Peak levels of Dpp and Scw signaling at the dorsal midline lead to the phosphorylation and nuclear transport of two Smad transcription factors, Mad and Medea med Mad and Medea, along with the Zen homeodomain regulator, activate a number of genes required for the differentiation and function of the amnioserosa, including hindsight hnt and Doc a Tbx6 transcription factor Lower levels of Dpp plus Scw signaling activate a number of regulatory genes throughout the dorsal ectoderm, including tailup tup , u-shaped ush , pannier pnr , and schnurri shn These genes respond to lower levels of Mad plus Medea, or as drawn in the diagram, respond solely to a particular activator complex containing Medea.

Shn functions as a repressor that maintains the boundary between the neurogenic ectoderm and dorsal ectoderm by repressing brk 43 and neurogenic genes such as msh , which is expressed in the dorsal-most regions of the neurogenic ectoderm The Dorsal nuclear gradient leads to the differential expression of nearly 50 genes across the dorsal—ventral axis e. Roughly half the genes encode sequence-specific transcription factors, whereas the other half encodes components of cell signaling pathways. Cis-regulatory modules have been identified, and in many cases characterized, for about half of the zygotically expressed genes shown in the network.

Twi is an immediate early target gene of the Dorsal gradient e. It is activated by high levels of the gradient in ventral regions that form mesoderm. Twi regulates nearly half of the known Dorsal target genes, including most of those activated in the mesoderm and ventral regions of the neurogenic ectoderm. Dorsal and Twi function in an additive fashion to activate a number of genes in the ventral mesoderm before the onset of gastrulation e.

The Sna repressor is also deployed during the initial phases of the dorsal—ventral network. Like Twi, Sna regulates a large number of Dorsal target genes, particularly those expressed in the neurogenic and dorsal ectoderms e. In principle, these genes can be activated in the mesoderm by high levels of Dorsal but are kept off by the Sna repressor. Thus, dorsal—ventral patterning begins with an interlocking set of three transcription factors, Dorsal, Twi, and Sna. There are two overall features of the dorsal—ventral patterning network that we wish to emphasize, because they reveal differences and similarities with the sea urchin endomesoderm network discussed above.

First, during the early phases of development, there is the extensive use in the Drosophila dorsal—ventral patterning network of transcriptional repressors to establish boundaries of gene expression Fig. In the sea urchin network, although there are negative feedbacks and cross-regulations within territories, the boundaries are set by lineage and signaling interfaces.

Second, during this initial phase, there are very few examples of positive autofeedback or positive cross-regulatory feedback loops such as that in Fig. We argue that this specific circuitry has evolved to generate dynamic and transient patterns of gene expression in syncytial embryos, which essentially lack intercellular signaling mechanisms.

In contrast, after cellularization, the circuitry exhibits autoregulation and positive feedback loops involving intercellular signaling pathways Fig. These loops implement stable networks of cellular differentiation during gastrulation, and they are essentially similar to those seen in the sea urchin endomesoderm network. Repression and Formation of Gene Expression Boundaries. Transcriptional repression plays a pervasive role in the initial patterning of the embryo.

Four of the seven regulatory genes activated by the Dorsal gradient in syncytial embryos encode sequence-specific repressors Sna, Brinker, Vnd, and Ind. The Sna repressor creates a boundary between the presumptive mesoderm and neurogenic ectoderm by excluding the expression of at least seven different Dorsal target genes e.

Sna is transiently expressed in the mesoderm and lost from the mesoderm during gastrulation The Brinker repressor helps create a boundary between the neurogenic and dorsal ectoderms by repressing Dpp signaling components that are required for the differentiation of specialized dorsal tissues such as the amnioserosa 41 , Brinker maintains this boundary by repressing the Schnurri gene 43 , which encodes a repressor that establishes the dorsal limits of neurogenic genes e. Regulatory Circuitry Following Cellularization.

Stable circuits of autoregulation and positive feedback loops are not seen until the onset of gastrulation. The regulatory gene sim coordinates a subcircuit, or kernel, within the dorsal—ventral network that is essential for the patterning of the neurogenic ectoderm. Sim is activated by a combination of Dorsal, Twi, and Notch signaling 44 ,

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