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1.  Dual mode of embryonic development is highlighted by expression and function of Nasonia pair-rule genes 
eLife  2014;3:e01440.
Embryonic anterior–posterior patterning is well understood in Drosophila, which uses ‘long germ’ embryogenesis, in which all segments are patterned before cellularization. In contrast, most insects use ‘short germ’ embryogenesis, wherein only head and thorax are patterned in a syncytial environment while the remainder of the embryo is generated after cellularization. We use the wasp Nasonia (Nv) to address how the transition from short to long germ embryogenesis occurred. Maternal and gap gene expression in Nasonia suggest long germ embryogenesis. However, the Nasonia pair-rule genes even-skipped, odd-skipped, runt and hairy are all expressed as early blastoderm pair-rule stripes and late-forming posterior stripes. Knockdown of Nv eve, odd or h causes loss of alternate segments at the anterior and complete loss of abdominal segments. We propose that Nasonia uses a mixed mode of segmentation wherein pair-rule genes pattern the embryo in a manner resembling Drosophila at the anterior and ancestral Tribolium at the posterior.
DOI: http://dx.doi.org/10.7554/eLife.01440.001
eLife digest
Networks of genes that work together are widespread in nature. The conservation of individual genes across species and the tendency of their networks to stick together is a sign that they are working efficiently. Furthermore, it is common for existing gene networks to be adapted to perform new tasks, instead of new networks being invented every time a similar but distinct demand arises. One important question is: how can evolution use the same building blocks—such as the genes in a functioning network—in different ways to achieve new outcomes?
The gene network that sets up the ‘body plan’ of insects during development has been well studied, most deeply in the fruit fly, Drosophila. Like all insects, the body of a fruit fly is divided into three main parts—the head, the thorax and the abdomen—and each of these parts is made up of several smaller segments. There is a remarkable diversity of insect body plans in nature, and yet, these seem to arise from the same gene networks in the embryo.
When a Drosophila embryo is growing into a larva, all the different body segments develop at the same time. In most other insects, however, segments of the abdomen emerge later and sequentially during the development process. The ancestors of most insects are also thought to have developed in this way, which is known as ‘short germ embryogenesis’. So how did the so-called ‘long germ embryogenesis’, as observed in Drosophila, evolve from the short germ embryogenesis that is observed in most other insects?
The gene network that controls development includes the ‘pair-rule genes’ that are expressed in a pattern of alternating stripes that wrap around, top to bottom, along most of the length of the embryo. These stripes mark where the edges of each body segment will eventually develop. In fruit flies, this pattern extends along the entire length of the embryo and the stripes all appear at one time. However, in the abdominal region of short germ insects, the pair-rule genes are expressed in waves that pass through the posterior region as it grows, with new segments being added one behind the other.
Now, Rosenberg et al. have attempted to explain how the same genes can be used to direct the segmentation process in such different ways by studying another long germ insect species, the jewel wasp. Analysis of the expression of pair-rule genes in the jewel wasp shows that it uses a mixed strategy to control segmentation. The development of segments at the front of its body is directed in the same way as the fruit fly, with all these segments laid down together. However, the segments at the rear of the body are only patterned later, one after the other, like most other insects.
The work of Rosenberg et al. suggests that the jewel wasp represents an intermediate step between ancestral insects and Drosophila in the evolution of the gene network that patterns the ‘body plan’. Identifying and studying these intermediate forms allows us to understand the ways in which evolution can innovate by building upon what has come before.
DOI: http://dx.doi.org/10.7554/eLife.01440.002
doi:10.7554/eLife.01440
PMCID: PMC3941026  PMID: 24599282
Nasonia vitripennis; Tribolium; embryonic patterning; evolution; segmentation; pair-rule genes; D. melanogaster; other
2.  Caudal Regulates the Spatiotemporal Dynamics of Pair-Rule Waves in Tribolium 
PLoS Genetics  2014;10(10):e1004677.
In the short-germ beetle Tribolium castaneum, waves of pair-rule gene expression propagate from the posterior end of the embryo towards the anterior and eventually freeze into stable stripes, partitioning the anterior-posterior axis into segments. Similar waves in vertebrates are assumed to arise due to the modulation of a molecular clock by a posterior-to-anterior frequency gradient. However, neither a molecular candidate nor a functional role has been identified to date for such a frequency gradient, either in vertebrates or elsewhere. Here we provide evidence that the posterior gradient of Tc-caudal expression regulates the oscillation frequency of pair-rule gene expression in Tribolium. We show this by analyzing the spatiotemporal dynamics of Tc-even-skipped expression in strong and mild knockdown of Tc-caudal, and by correlating the extension, level and slope of the Tc-caudal expression gradient to the spatiotemporal dynamics of Tc-even-skipped expression in wild type as well as in different RNAi knockdowns of Tc-caudal regulators. Further, we show that besides its absolute importance for stripe generation in the static phase of the Tribolium blastoderm, a frequency gradient might serve as a buffer against noise during axis elongation phase in Tribolium as well as vertebrates. Our results highlight the role of frequency gradients in pattern formation.
Author Summary
One of the most popular problems in development is how the anterior-posterior axis of vertebrates, arthropods and annelids is partitioned into segments. In vertebrates, and recently shown in the beetle Tribolium castaneum, segments are demarcated by means of gene expression waves that propagate from posterior to anterior as the embryo elongates. These waves are assumed to arise due to the regulation of a molecular clock by a frequency gradient. However, to date, neither a candidate nor a functional role has been identified for such a frequency gradient. Here we provide evidence that a static expression gradient of caudal regulates pair-rule oscillations during blastoderm stage in Tribolium. In such a static setup, a frequency gradient is essential to convert clock oscillations into a striped pattern. We further show that a frequency gradient might be essential even in the presence of axis elongation as a buffer against noise. Our work also provides the best evidence to date that Caudal acts as a type of morphogen gradient in the blastoderm of short-germ arthropods; however, Caudal seems to convey positional information through frequency regulation of pair-rule oscillations, rather than through threshold concentration levels in the gradient.
doi:10.1371/journal.pgen.1004677
PMCID: PMC4199486  PMID: 25329152
3.  Analysis of an even-skipped rescue transgene reveals both composite and discrete neuronal and early blastoderm enhancers, and multi-stripe positioning by gap gene repressor gradients* 
Development (Cambridge, England)  1999;126(11):2527-2538.
SUMMARY
The entire functional even-skipped locus of Drosophila melanogaster is contained within a 16 kilobase region. As a transgene, this region is capable of rescuing even-skipped mutant flies to fertile adulthood. Detailed analysis of the 7.7 kb of regulatory DNA 3′ of the transcription unit revealed ten novel, independently regulated patterns. Most of these patterns are driven by non-overlapping regulatory elements, including ones for syncytial blastoderm stage stripes 1 and 5, while a single element specifies both stripes 4 and 6. Expression analysis in gap gene mutants showed that stripe 5 is restricted anteriorly by Krüppel and posteriorly by giant, the same repressors that regulate stripe 2. Consistent with the coregulation of stripes 4 and 6 by a single cis-element, both the anterior border of stripe 4 and the posterior border of stripe 6 are set by zygotic hunchback, and the region between the two stripes is ‘carved out’ by knirps. Thus the boundaries of stripes 4 and 6 are set through negative regulation by the same gap gene domains that regulate stripes 3 and 7 (Small, S., Blair, A. and Levine, M. (1996) Dev. Biol.175, 314–24), but at different concentrations. The 3′ region also contains a single element for neurogenic expression in ganglion mother cells 4-2a and 1-1a, and neurons derived from them (RP2, a/pCC), suggesting common regulators in these lineages. In contrast, separable elements were found for expression in EL neurons, U/CQ neurons and the mesoderm. The even-skipped3′ untranslated region is required to maintain late stage protein expression in RP2 and a/pCC neurons, and appears to affect protein levels rather than mRNA levels. Additionally, a strong pairing-sensitive repression element was localized to the 3′ end of the locus, but was not found to contribute to efficient functional rescue.
PMCID: PMC2778309  PMID: 10226011
even-skipped; CNS; Pattern formation; Segmentation; Translational control; Chromatin
4.  Expression of pair rule gene orthologs in the blastoderm of a myriapod: evidence for pair rule-like mechanisms? 
Background
A hallmark of Drosophila segmentation is the stepwise subdivision of the body into smaller and smaller units, and finally into the segments. This is achieved by the function of the well-understood segmentation gene cascade. The first molecular sign of a segmented body appears with the action of the pair rule genes, which are expressed as transversal stripes in alternating segments. Drosophila development, however, is derived, and in most other arthropods only the anterior body is patterned (almost) simultaneously from a pre-existing field of cells; posterior segments are added sequentially from a posterior segment addition zone. A long-standing question is to what extent segmentation mechanisms known from Drosophila may be conserved in short-germ arthropods. Despite the derived developmental modes, it appears more likely that conserved mechanisms can be found in anterior patterning.
Results
Expression analysis of pair rule gene orthologs in the blastoderm of the pill millipede Glomeris marginata (Myriapoda: Diplopoda) suggests that these genes are generally involved in segmenting the anterior embryo. We find that the Glomeris pairberry-1 ( pby-1) gene is expressed in a pair rule pattern that is also found in insects and a chelicerate, the mite Tetraynchus urticae. Other Glomeris pair rule gene orthologs are expressed in double segment wide domains in the blastoderm, which at subsequent stages split into two stripes in adjacent segments.
Conclusions
The expression patterns of the millipede pair rule gene orthologs resemble pair rule patterning in Drosophila and other insects, and thus represent evidence for the presence of an ancestral pair rule-like mechanism in myriapods. We discuss the possibilities that blastoderm patterning may be conserved in long-germ and short-germ arthropods, and that a posterior double segmental mechanism may be present in short-germ arthropods.
doi:10.1186/1471-213X-12-15
PMCID: PMC3477074  PMID: 22595029
Evolution; Pair rule patterning; Segmentation; Paired; Even-skipped; Runt; Hairy; Odd-paired; Sloppy-paired; Odd-skipped
5.  Transcriptional Control in the Segmentation Gene Network of Drosophila 
PLoS Biology  2004;2(9):e271.
The segmentation gene network of Drosophila consists of maternal and zygotic factors that generate, by transcriptional (cross-) regulation, expression patterns of increasing complexity along the anterior-posterior axis of the embryo. Using known binding site information for maternal and zygotic gap transcription factors, the computer algorithm Ahab recovers known segmentation control elements (modules) with excellent success and predicts many novel modules within the network and genome-wide. We show that novel module predictions are highly enriched in the network and typically clustered proximal to the promoter, not only upstream, but also in intronic space and downstream. When placed upstream of a reporter gene, they consistently drive patterned blastoderm expression, in most cases faithfully producing one or more pattern elements of the endogenous gene. Moreover, we demonstrate for the entire set of known and newly validated modules that Ahab's prediction of binding sites correlates well with the expression patterns produced by the modules, revealing basic rules governing their composition. Specifically, we show that maternal factors consistently act as activators and that gap factors act as repressors, except for the bimodal factor Hunchback. Our data suggest a simple context-dependent rule for its switch from repressive to activating function. Overall, the composition of modules appears well fitted to the spatiotemporal distribution of their positive and negative input factors. Finally, by comparing Ahab predictions with different categories of transcription factor input, we confirm the global regulatory structure of the segmentation gene network, but find odd skipped behaving like a primary pair-rule gene. The study expands our knowledge of the segmentation gene network by increasing the number of experimentally tested modules by 50%. For the first time, the entire set of validated modules is analyzed for binding site composition under a uniform set of criteria, permitting the definition of basic composition rules. The study demonstrates that computational methods are a powerful complement to experimental approaches in the analysis of transcription networks.
Starting with known transcription binding site information these researchers use a the computer algorithm, Ahab, to recover known control elements and find novel modules within the genome
doi:10.1371/journal.pbio.0020271
PMCID: PMC514885  PMID: 15340490
6.  THE NUCLEAR RECEPTOR E75A HAS A NOVEL PAIR-RULE-LIKE FUNCTION IN PATTERNING THE MILKWEED BUG, ONCOPELTUS FASCIATUS 
Developmental biology  2009;334(1):300-310.
Genetic studies of the fruit fly Drosophila have revealed a hierarchy of segmentation genes (maternal, gap, pair-rule and HOX) that subdivide the syncytial blastoderm into sequentially finer scale coordinates. Within this hierarchy, the pair-rule genes translate gradients of information into periodic stripes of expression. How pair-rule genes function during the progressive mode of segmentation seen in short and intermediate-germ insects is an ongoing question. Here we report that the nuclear receptor Of’E75A is expressed with double segment periodicity in the head and thorax. In the abdomen, Of’E75A is expressed in a unique pattern during posterior elongation, and briefly resembles a sequence that is typical of pair-rule genes. Depletion of Of’E75A mRNA caused loss of a subset of odd-numbered parasegments, as well as parasegment 6. Because these parasegments straddle segment boundaries, we observe fusions between adjacent segments. Finally, expression of Of’E75A in the blastoderm requires even-skipped, which is a gap gene in Oncopeltus. These data show that the function of Of’E75A during embryogenesis shares many properties with canonical pair-rule genes in other insects. They further suggest that parasegment specification may occur through irregular and episodic pair-rule-like activity.
doi:10.1016/j.ydbio.2009.06.038
PMCID: PMC2749522  PMID: 19580803
Pair-rule; Oncopeltus fasciatus; nuclear receptor; ecdysone-response; E75; intermediate-germ insect; segmentation; milkweed bug
7.  Mechanisms of gap gene expression canalization in the Drosophila blastoderm 
BMC Systems Biology  2011;5:118.
Background
Extensive variation in early gap gene expression in the Drosophila blastoderm is reduced over time because of gap gene cross regulation. This phenomenon is a manifestation of canalization, the ability of an organism to produce a consistent phenotype despite variations in genotype or environment. The canalization of gap gene expression can be understood as arising from the actions of attractors in the gap gene dynamical system.
Results
In order to better understand the processes of developmental robustness and canalization in the early Drosophila embryo, we investigated the dynamical effects of varying spatial profiles of Bicoid protein concentration on the formation of the expression border of the gap gene hunchback. At several positions on the anterior-posterior axis of the embryo, we analyzed attractors and their basins of attraction in a dynamical model describing expression of four gap genes with the Bicoid concentration profile accounted as a given input in the model equations. This model was tested against a family of Bicoid gradients obtained from individual embryos. These gradients were normalized by two independent methods, which are based on distinct biological hypotheses and provide different magnitudes for Bicoid spatial variability. We showed how the border formation is dictated by the biological initial conditions (the concentration gradient of maternal Hunchback protein) being attracted to specific attracting sets in a local vicinity of the border. Different types of these attracting sets (point attractors or one dimensional attracting manifolds) define several possible mechanisms of border formation. The hunchback border formation is associated with intersection of the spatial gradient of the maternal Hunchback protein and a boundary between the attraction basins of two different point attractors. We demonstrated how the positional variability for hunchback is related to the corresponding variability of the basin boundaries. The observed reduction in variability of the hunchback gene expression can be accounted for by specific geometrical properties of the basin boundaries.
Conclusion
We clarified the mechanisms of gap gene expression canalization in early Drosophila embryos. These mechanisms were specified in the case of hunchback in well defined terms of the dynamical system theory.
doi:10.1186/1752-0509-5-118
PMCID: PMC3398401  PMID: 21794172
8.  Expression of myriapod pair rule gene orthologs 
EvoDevo  2011;2:5.
Background
Segmentation is a hallmark of the arthropods; most knowledge about the molecular basis of arthropod segmentation comes from work on the fly Drosophila melanogaster. In this species a hierarchic cascade of segmentation genes subdivides the blastoderm stepwise into single segment wide regions. However, segmentation in the fly is a derived feature since all segments form virtually simultaneously. Conversely, in the vast majority of arthropods the posterior segments form one at a time from a posterior pre-segmental zone. The pair rule genes (PRGs) comprise an important level of the Drosophila segmentation gene cascade and are indeed the first genes that are expressed in typical transverse stripes in the early embryo. Information on expression and function of PRGs outside the insects, however, is scarce.
Results
Here we present the expression of the pair rule gene orthologs in the pill millipede Glomeris marginata (Myriapoda: Diplopoda). We find evidence that these genes are involved in segmentation and that components of the hierarchic interaction of the gene network as found in insects may be conserved. We further provide evidence that segments are formed in a single-segment periodicity rather than in pairs of two like in another myriapod, the centipede Strigamia maritima. Finally we show that decoupling of dorsal and ventral segmentation in Glomeris appears already at the level of the PRGs.
Conclusions
Although the pair rule gene network is partially conserved among insects and myriapods, some aspects of PRG interaction are, as suggested by expression pattern analysis, convergent, even within the Myriapoda. Conserved expression patterns of PRGs in insects and myriapods, however, may represent ancestral features involved in segmenting the arthropod ancestor.
doi:10.1186/2041-9139-2-5
PMCID: PMC3058060  PMID: 21352542
9.  A Precise Bicoid Gradient Is Nonessential during Cycles 11–13 for Precise Patterning in the Drosophila Blastoderm 
PLoS ONE  2008;3(11):e3651.
Background
During development, embryos decode maternal morphogen inputs into highly precise zygotic gene expression. The discovery of the morphogen Bicoid and its profound effect on developmental programming in the Drosophila embryo has been a cornerstone in understanding the decoding of maternal inputs. Bicoid has been described as a classical morphogen that forms a concentration gradient along the antero-posterior axis of the embryo by diffusion and initiates expression of target genes in a concentration-dependent manner in the syncytial blastoderm. Recent work has emphasized the stability of the Bicoid gradient as a function of egg length and the role of nuclear dynamics in maintaining the Bicoid gradient. Bicoid and nuclear dynamics were observed but not modulated under the ideal conditions used previously. Therefore, it has not been tested explicitly whether a temporally stable Bicoid gradient prior to cellularization is required for precise patterning.
Principal Findings
Here, we modulate both nuclear dynamics and the Bicoid gradient using laminar flows of different temperature in a microfluidic device to determine if stability of the Bicoid gradient prior to cellularization is essential for precise patterning. Dramatic motion of both cytoplasm and nuclei was observed prior to cellularization, and the Bicoid gradient was disrupted by nuclear motion and was highly abnormal as a function of egg length. Despite an abnormal Bicoid gradient during cycles 11–13, Even-skipped patterning in these embryos remained precise.
Conclusions
These results indicate that the stability of the Bicoid gradient as a function of egg length is nonessential during syncytial blastoderm stages. Further, presumably no gradient formed by simple diffusion on the scale of egg length could be responsible for the robust antero-posterior patterning observed, as severe cytoplasmic and nuclear motion would disrupt such a gradient. Additional mechanisms for how the embryo could sense its dimensions and interpret the Bicoid gradient are discussed.
doi:10.1371/journal.pone.0003651
PMCID: PMC2578877  PMID: 18989373
10.  Characterization of the Drosophila segment determination morphome 
Developmental biology  2007;313(2):844-862.
Here we characterize the expression of the full system of genes which control the segmentation morphogenetic field of Drosophila at the protein level in one dimension. The data used for this characterization are quantitative with cellular resolution in space and about 6 min in time. We present the full quantitative profiles of all 14 segmentation genes which act before the onset of gastrulation. The expression patterns of these genes are first characterized in terms of their average or typical behavior. At this level, the expression of all of the genes has been integrated into a single atlas of gene expression in which the expression levels of all genes in each cell are specified. We show that expression domains do not arise synchronously, but rather each domain has its own specific dynamics of formation. Moreover, we show that the expression domains shift position in the direction of the cephalic furrow, such that domains in the anlage of the segmented germ band shift anteriorly while those in the presumptive head shift posteriorly. The expression atlas of integrated data is very close to the expression profiles of individual embryos during the latter part of the blastoderm stage. At earlier times gap gene domains show considerable variation in amplitude, and significant positional variability. Nevertheless, an average early gap domain is close to that of a median individual. In contrast, we show that there is a diversity of developmental trajectories among pair-rule genes at a variety of levels, including the order of domain formation and positional accuracy. We further show that this variation is dynamically reduced, or canalized, over time. As the first quantitatively characterized morphogenetic field, this system and its behavior constitute an extraordinarily rich set of materials for the study of canalization and embryonic regulation at the molecular level.
doi:10.1016/j.ydbio.2007.10.037
PMCID: PMC2254320  PMID: 18067886
Drosophila embryo; Segmentation genes; Blastoderm; Gene expression; Quantitative expression data; Positional information
11.  Canalization of Gene Expression and Domain Shifts in the Drosophila Blastoderm by Dynamical Attractors 
PLoS Computational Biology  2009;5(3):e1000303.
The variation in the expression patterns of the gap genes in the blastoderm of the fruit fly Drosophila melanogaster reduces over time as a result of cross regulation between these genes, a fact that we have demonstrated in an accompanying article in PLoS Biology (see Manu et al., doi:10.1371/journal.pbio.1000049). This biologically essential process is an example of the phenomenon known as canalization. It has been suggested that the developmental trajectory of a wild-type organism is inherently stable, and that canalization is a manifestation of this property. Although the role of gap genes in the canalization process was established by correctly predicting the response of the system to particular perturbations, the stability of the developmental trajectory remains to be investigated. For many years, it has been speculated that stability against perturbations during development can be described by dynamical systems having attracting sets that drive reductions of volume in phase space. In this paper, we show that both the reduction in variability of gap gene expression as well as shifts in the position of posterior gap gene domains are the result of the actions of attractors in the gap gene dynamical system. Two biologically distinct dynamical regions exist in the early embryo, separated by a bifurcation at 53% egg length. In the anterior region, reduction in variation occurs because of stability induced by point attractors, while in the posterior, the stability of the developmental trajectory arises from a one-dimensional attracting manifold. This manifold also controls a previously characterized anterior shift of posterior region gap domains. Our analysis shows that the complex phenomena of canalization and pattern formation in the Drosophila blastoderm can be understood in terms of the qualitative features of the dynamical system. The result confirms the idea that attractors are important for developmental stability and shows a richer variety of dynamical attractors in developmental systems than has been previously recognized.
Author Summary
C. H. Waddington predicted in 1942 that networks of chemical reactions in embryos can counteract the effects of variable developmental conditions to produce reliable outcomes. The experimental signature of this process, called “canalization,” is the reduction of the variation of the concentrations of molecular determinants between individuals over time. Recently, Waddington's prediction was confirmed in embryos of the fruit fly Drosophila by observing the expression of a network of genes involved in generating the basic segmented body plan of this animal. Nevertheless, the details of how interactions within this genetic network reduced variation were still not understood. We use an accurate mathematical model of a part of this genetic network to demonstrate how canalization comes about. Our results show that coupled chemical reactions having multiple steady states, or attractors, can account for the reduction of variation in development. The variation reduction process can be driven not only by chemical steady states, but also by special pathways of motion through chemical concentration space to which neighboring pathways converge. These results constitute a precise mathematical characterization of a healing process in the fruit fly embryo.
doi:10.1371/journal.pcbi.1000303
PMCID: PMC2646127  PMID: 19282965
12.  Tc-knirps plays different roles in the specification of antennal and mandibular parasegment boundaries and is regulated by a pair-rule gene in the beetle Tribolium castaneum 
Background
The Drosophila larval head is evolutionarily derived at the genetic and morphological level. In the beetle Tribolium castaneum, development of the larval head more closely resembles the ancestral arthropod condition. Unlike in Drosophila, a knirps homologue (Tc-kni) is required for development of the antennae and mandibles. However, published Tc-kni data are restricted to cuticle phenotypes and Tc-even-skipped and Tc-wingless stainings in knockdown embryos. Hence, it has remained unclear whether the entire antennal and mandibular segments depend on Tc-kni function, and whether the intervening intercalary segment is formed completely. We address these questions with a detailed examination of Tc-kni function.
Results
By examining the expression of marker genes in RNAi embryos, we show that Tc-kni is required only for the formation of the posterior parts of the antennal and mandibular segments (i.e. the parasegmental boundaries). Moreover, we find that the role of Tc-kni is distinct in these segments: Tc-kni is required for the initiation of the antennal parasegment boundary, but only for the maintenance of the mandibular parasegmental boundary. Surprisingly, Tc-kni controls the timing of expression of the Hox gene Tc-labial in the intercalary segment, although this segment does form in the absence of Tc-kni function. Unexpectedly, we find that the pair-rule gene Tc-even-skipped helps set the posterior boundary of Tc-kni expression in the mandible. Using the mutant antennaless, a likely regulatory Null mutation at the Tc-kni locus, we provide evidence that our RNAi studies represent a Null situation.
Conclusions
Tc-kni is required for the initiation of the antennal and the maintenance of the mandibular parasegmental boundaries. Tc-kni is not required for specification of the anterior regions of these segments, nor the intervening intercalary segment, confirming that Tc-kni is not a canonical ‘gap-gene’. Our finding that a gap gene orthologue is regulated by a pair rule gene adds to the view that the segmentation gene hierarchies differ between Tribolium and Drosophila upstream of the pair rule gene level. In Tribolium, as in Drosophila, head and trunk segmentation gene networks cooperate to pattern the mandibular segment, albeit involving Tc-kni as novel component.
doi:10.1186/1471-213X-13-25
PMCID: PMC3698154  PMID: 23777260
Knirps; Head gap gene; Tribolium; Antenna; Mandible; Intercalary segment
13.  Role of abd-A and Abd-B in Development of Abdominal Epithelia Breaks Posterior Prevalence Rule 
PLoS Genetics  2014;10(10):e1004717.
Hox genes that determine anteroposterior body axis formation in all bilaterians are often found to have partially overlapping expression pattern. Since posterior genes dominate over anterior Hox genes in the region of co-expression, the anterior Hox genes are thought to have no function in such regions. In this study we show that two Hox genes have distinct and essential functions in the same cell. In Drosophila, the three Hox genes of the bithorax complex, Ubx, abd-A and Abd-B, show coexpression during embryonic development. Here, we show that in early pupal abdominal epithelia, Ubx does not coexpress with abd-A and Abd-B, while abd-A and Abd-B continue to coexpress in the same nuclei. The abd-A and Abd-B are expressed in both histoblast nest cells and larval epithelial cells of early pupal abdominal epithelia. Further functional studies demonstrate that abd-A is required in histoblast nest cells for their proliferation and suppression of Ubx to prevent first abdominal segment like features in posterior segments while in larval epithelial cells it is required for their elimination. We also observed that these functions of abd-A are required in its exclusive as well as the coexpression domain with that of Abd-B. The expression of Abd-B is required in histoblast nest cells for their identity while it is dispensable in the larval epithelial cells. The higher level of Abd-B in the seventh abdominal segment, that down-regulates abd-A expression, leads this segment to be absent in males or of smaller size in females. We also show that abd-A in histoblast nest cells positively regulates expression of wingless for the formation of the abdominal epithelia. Our study reveals an exception to the rule of posterior prevalence and shows that two different Hox genes have distinct functions in the same cell, which is essential for the development of abdominal epithelia.
Author Summary
The spatially non-overlapping function of Hox genes is known to determine Antero-posterior body axis in all the bilaterians. The expression of Hox genes is found to be overlapping in several cases. According to the posterior prevalence rule, posterior Hox genes suppress the function of anterior Hox genes in the overlapping expression domains. Our findings show an exception to the rule of posterior prevalence. We show that in the overlapping expression domains of abd-A and Abd-B in early pupal abdominal epithelia, both the genes have essential roles. While abd-A is required for cell proliferation, Abd-B determines the segmental identity.
doi:10.1371/journal.pgen.1004717
PMCID: PMC4207640  PMID: 25340649
14.  Three-dimensional morphology and gene expression in the Drosophila blastoderm at cellular resolution I: data acquisition pipeline 
Genome Biology  2006;7(12):R123.
A suite of methods that provide the first quantitative three-dimensional description of gene expression and morphology with cellular resolution in whole Drosophila embryos is described.
Background
To model and thoroughly understand animal transcription networks, it is essential to derive accurate spatial and temporal descriptions of developing gene expression patterns with cellular resolution.
Results
Here we describe a suite of methods that provide the first quantitative three-dimensional description of gene expression and morphology at cellular resolution in whole embryos. A database containing information derived from 1,282 embryos is released that describes the mRNA expression of 22 genes at multiple time points in the Drosophila blastoderm. We demonstrate that our methods are sufficiently accurate to detect previously undescribed features of morphology and gene expression. The cellular blastoderm is shown to have an intricate morphology of nuclear density patterns and apical/basal displacements that correlate with later well-known morphological features. Pair rule gene expression stripes, generally considered to specify patterning only along the anterior/posterior body axis, are shown to have complex changes in stripe location, stripe curvature, and expression level along the dorsal/ventral axis. Pair rule genes are also found to not always maintain the same register to each other.
Conclusion
The application of these quantitative methods to other developmental systems will likely reveal many other previously unknown features and provide a more rigorous understanding of developmental regulatory networks.
doi:10.1186/gb-2006-7-12-r123
PMCID: PMC1794436  PMID: 17184546
15.  Dissecting sources of quantitative gene expression pattern divergence between Drosophila species 
The function of a transcriptional circuit is compared in three closely related species of Drosophila. Using quantitative imaging of gene expression, targeted transgenic reporter fly lines, and a computational framework, the sources of their differing expression outputs are identified.
The logic of the transcriptional circuit controlling expression of the embryonic hunchback posterior stripe is highly conserved between three Drosophila species (D. melanogaster, D. yakuba, and D. pseudoobscura), despite observed differences in the hunchback posterior stripe expression pattern.Quantitative expression differences in the hunchback posterior stripe are largely, but not entirely, due to changes in the expression patterns of upstream regulators.The set of orthologous cis-regulatory elements (CREs) underlying this circuit direct similar expression patterns in concordance with previous qualitative studies; however, the expression patterns they direct are quantitatively distinct.These results indicate that small-scale sequence changes in CREs can impact their function and has broad implications for understanding the importance of transcription factor binding site architecture in CRE function.
Gene expression patterns can diverge between species due to changes in a gene's regulatory DNA or changes in the proteins, e.g., transcription factors (TFs), that regulate the gene. We developed a modeling framework to uncover the sources of expression differences in blastoderm embryos of three Drosophila species, focusing on the regulatory circuit controlling expression of the hunchback (hb) posterior stripe. Using this framework and cellular-resolution expression measurements of hb and its regulating TFs, we found that changes in the expression patterns of hb's TFs account for much of the expression divergence. We confirmed our predictions using transgenic D. melanogaster lines, which demonstrate that this set of orthologous cis-regulatory elements (CREs) direct similar, but not identical, expression patterns. We related expression pattern differences to sequence changes in the CRE using a calculation of the CRE's TF binding site content. By applying this calculation in both the transgenic and endogenous contexts, we found that changes in binding site content affect sensitivity to regulating TFs and that compensatory evolution may occur in circuit components other than the CRE.
doi:10.1038/msb.2012.35
PMCID: PMC3435502  PMID: 22893002
cis-regulatory elements; gene expression divergence; transcriptional regulatory network
16.  A Software Tool to Model Genetic Regulatory Networks. Applications to the Modeling of Threshold Phenomena and of Spatial Patterning in Drosophila 
PLoS ONE  2010;5(5):e10743.
We present a general methodology in order to build mathematical models of genetic regulatory networks. This approach is based on the mass action law and on the Jacob and Monod operon model. The mathematical models are built symbolically by the Mathematica software package GeneticNetworks. This package accepts as input the interaction graphs of the transcriptional activators and repressors of a biological process and, as output, gives the mathematical model in the form of a system of ordinary differential equations. All the relevant biological parameters are chosen automatically by the software. Within this framework, we show that concentration dependent threshold effects in biology emerge from the catalytic properties of genes and its associated conservation laws. We apply this methodology to the segment patterning in Drosophila early development and we calibrate the genetic transcriptional network responsible for the patterning of the gap gene proteins Hunchback and Knirps, along the antero-posterior axis of the Drosophila embryo. In this approach, the zygotically produced proteins Hunchback and Knirps do not diffuse along the antero-posterior axis of the embryo of Drosophila, developing a spatial pattern due to concentration dependent thresholds. This shows that patterning at the gap genes stage can be explained by the concentration gradients along the embryo of the transcriptional regulators.
doi:10.1371/journal.pone.0010743
PMCID: PMC2877713  PMID: 20523731
17.  Wnt/β-catenin signaling integrates patterning and metabolism of the insect growth zone 
Development (Cambridge, England)  2014;141(24):4740-4750.
Wnt/β-catenin and hedgehog (Hh) signaling are essential for transmitting signals across cell membranes in animal embryos. Early patterning of the principal insect model, Drosophila melanogaster, occurs in the syncytial blastoderm, where diffusion of transcription factors obviates the need for signaling pathways. However, in the cellularized growth zone of typical short germ insect embryos, signaling pathways are predicted to play a more fundamental role. Indeed, the Wnt/β-catenin pathway is required for posterior elongation in most arthropods, although which target genes are activated in this context remains elusive. Here, we use the short germ beetle Tribolium castaneum to investigate two Wnt and Hh signaling centers located in the head anlagen and in the growth zone of early embryos. We find that Wnt/β-catenin signaling acts upstream of Hh in the growth zone, whereas the opposite interaction occurs in the head. We determine the target gene sets of the Wnt/β-catenin and Hh pathways and find that the growth zone signaling center activates a much greater number of genes and that the Wnt and Hh target gene sets are essentially non-overlapping. The Wnt pathway activates key genes of all three germ layers, including pair-rule genes, and Tc-caudal and Tc-twist. Furthermore, the Wnt pathway is required for hindgut development and we identify Tc-senseless as a novel hindgut patterning gene required in the early growth zone. At the same time, Wnt acts on growth zone metabolism and cell division, thereby integrating growth with patterning. Posterior Hh signaling activates several genes potentially involved in a proteinase cascade of unknown function.
doi:10.1242/dev.112797
PMCID: PMC4299277  PMID: 25395458
Head; Growth zone; Segment addition zone; Wnt; Hedgehog; Gut; Senseless
18.  Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm  
PLoS Biology  2008;6(2):e27.
Identifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map sequences bound in Drosophila melanogaster embryos by the six maternal and gap transcription factors that initiate anterior–posterior patterning. We find that these sequence-specific DNA binding proteins bind with quantitatively different specificities to highly overlapping sets of several thousand genomic regions in blastoderm embryos. Specific high- and moderate-affinity in vitro recognition sequences for each factor are enriched in bound regions. This enrichment, however, is not sufficient to explain the pattern of binding in vivo and varies in a context-dependent manner, demonstrating that higher-order rules must govern targeting of transcription factors. The more highly bound regions include all of the over 40 well-characterized enhancers known to respond to these factors as well as several hundred putative new cis-regulatory modules clustered near developmental regulators and other genes with patterned expression at this stage of embryogenesis. The new targets include most of the microRNAs (miRNAs) transcribed in the blastoderm, as well as all major zygotically transcribed dorsal–ventral patterning genes, whose expression we show to be quantitatively modulated by anterior–posterior factors. In addition to these highly bound regions, there are several thousand regions that are reproducibly bound at lower levels. However, these poorly bound regions are, collectively, far more distant from genes transcribed in the blastoderm than highly bound regions; are preferentially found in protein-coding sequences; and are less conserved than highly bound regions. Together these observations suggest that many of these poorly bound regions are not involved in early-embryonic transcriptional regulation, and a significant proportion may be nonfunctional. Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets.
Author Summary
One of the largest classes of regulatory proteins in animals, sequence-specific DNA binding transcription factors determine in which cells genes will be expressed and so control the development of an animal from a single cell to a morphologically complex adult. Understanding how this process is coordinated depends on knowing the number and types of genes that each transcription factor binds and regulates. Using immunoprecipitation of in vivo crosslinked chromatin coupled with DNA microarray hybridization (ChIP/chip), we have determined the genomic binding sites in early embryos of six transcription factors that play a crucial role in early development of the fruit fly Drosophila melanogaster. We find that these proteins bind to several thousand genomic regions that lie close to approximately half the protein coding genes. Although this is a much larger number of genes than these factors are generally thought to regulate, we go on to show that whereas the more highly bound genes generally look to be functional targets, many of the genes bound at lower levels do not appear to be regulated by these factors. Our conclusions differ from those of other groups who have not distinguished between different levels of DNA binding in vivo using similar assays and who have generally assumed that all detected binding is functional.
ChIP/chip analysis indicates that sequence-specific transcription factors bind to overlapping sets of thousands of genomic regions in Drosophila embryos, but most regions are bound at low levels and many may not be functional targets of these factors.
doi:10.1371/journal.pbio.0060027
PMCID: PMC2235902  PMID: 18271625
19.  The Drosophila Gap Gene Network Is Composed of Two Parallel Toggle Switches 
PLoS ONE  2011;6(7):e21145.
Drosophila “gap” genes provide the first response to maternal gradients in the early fly embryo. Gap genes are expressed in a series of broad bands across the embryo during first hours of development. The gene network controlling the gap gene expression patterns includes inputs from maternal gradients and mutual repression between the gap genes themselves. In this study we propose a modular design for the gap gene network, involving two relatively independent network domains. The core of each network domain includes a toggle switch corresponding to a pair of mutually repressive gap genes, operated in space by maternal inputs. The toggle switches present in the gap network are evocative of the phage lambda switch, but they are operated positionally (in space) by the maternal gradients, so the synthesis rates for the competing components change along the embryo anterior-posterior axis. Dynamic model, constructed based on the proposed principle, with elements of fractional site occupancy, required 5–7 parameters to fit quantitative spatial expression data for gap gradients. The identified model solutions (parameter combinations) reproduced major dynamic features of the gap gradient system and explained gap expression in a variety of segmentation mutants.
doi:10.1371/journal.pone.0021145
PMCID: PMC3128594  PMID: 21747931
20.  Known Maternal Gradients are not Sufficient for the Establishment of Gap Domains in Drosophila melanogaster 
Mechanisms of development  2006;124(2):108-128.
Gap genes are among the first transcriptional targets of maternal morphogen gradients in the early Drosophila embryo. However, it remains unclear whether these gradients are indeed sufficient to establish the boundaries of localized gap gene expression patterns. In this study, we address this question using gap gene circuits, which are data-driven mathematical tools for extracting regulatory information from quantitative wild-type gene expression data. We present new, quantitative data on the mRNA expression patterns for the gap genes Krüppel (Kr), knirps (kni) and giant (gt) during the early blastoderm stage of Drosophila development. This data set shows significant differences in timing of gap gene expression compared to previous observations, and reveals that early gap gene expression is highly variable in both space and time. Gene circuit models fit to this data set were used for a detailed regulatory analysis of early gap gene expression. Our analysis shows that the proper balance of maternal repression and activation is essential for the correct positioning of gap domains, and that such balance can only be achieved for early expression of kni. In contrast, our results suggest that early expression of gt requires local neutralization of repressive input in the anterior region of the embryo, and that known maternal gradients are completely insufficient to position the boundaries of the early central Kr domain, or in fact any Kr-like domain in the central region of the blastoderm embryo. Based on this, we propose that unknown additional regulators must be involved in early gap gene regulation.
doi:10.1016/j.mod.2006.11.001
PMCID: PMC1992814  PMID: 17196796
segment determination; segmentation gene network; maternal morphogen gradient; gap gene; gene regulation; gene circuit; non-linear dynamics; simulated annealing; network inference
21.  Evolutionary flexibility of pair-rule patterning revealed by functional analysis of secondary pair-rule genes, paired and sloppy-paired in the short germ insect, Tribolium castaneum 
Developmental biology  2006;302(1):281-294.
In the Drosophila segmentation hierarchy, periodic expression of pair-rule genes translates gradients of regional information from maternal and gap genes into the segmental expression of segment polarity genes. In Tribolium, homologs of almost all the eight canonical Drosophila pair-rule genes are expressed in pair-rule domains, but only five have pair-rule functions. even-skipped, runt and odd-skipped act as primary pair-rule genes, while the functions of paired (prd) and sloppy-paired (slp) are secondary. Since secondary pair-rule genes directly regulate segment polarity genes in Drosophila, we analyzed Tc-prd and Tc-slp to determine the extent to which this paradigm is conserved in Tribolium. We found that the role of prd is conserved between Drosophila and Tribolium; it is required in both insects to activate engrailed in odd-numbered parasegments and wingless (wg) in even-numbered parasegments. Similarly, slp is required to activate wg in alternate parasegments and to maintain the remaining wg stripes in both insects. However, the parasegmental register for Tc-slp is opposite that of Drosophila slp1. Thus, while prd is functionally conserved, the fact that the register of slp function has evolved differently in the lineages leading to Drosophila and Tribolium reveals an unprecedented flexibility in pair-rule patterning.
doi:10.1016/j.ydbio.2006.09.037
PMCID: PMC1800430  PMID: 17054935
paired; sloppy-paired; segmentation; pair-rule gene; Tribolium castaneum
22.  Non-additive interactions involving two distinct elements mediate sloppy-paired regulation by pair-rule transcription factors 
Developmental biology  2010;344(2):1048-1059.
The relatively simple combinatorial rules responsible for establishing the initial metameric expression of sloppy-paired-1 (slp1) in the Drosophila blastoderm embryo make this system an attractive model for investigating the mechanism of regulation by pair rule transcription factors. This investigation of slp1 cis-regulatory architecture identifies two distinct elements, a proximal early stripe element (PESE) and a distal early stripe element (DESE) located from −3.1 kb to −2.5 kb and from −8.1 kb to −7.1 kb upstream of the slp1 promoter, respectively, that mediate this early regulation. The proximal element expresses only even-numbered stripes and mediates repression by Even-skipped (Eve) as well as by the combination of Runt and Fushi-tarazu (Ftz). A 272 basepair sub-element of PESE retains Eve-dependent repression, but is expressed throughout the even-numbered parasegments due to the loss of repression by Runt and Ftz. In contrast, the distal element expresses both odd and even-numbered stripes and also drives inappropriate expression in the anterior half of the odd-numbered parasegments due to an inability to respond to repression by Eve. Importantly, a composite reporter gene containing both early stripe elements recapitulates pair-rule gene-dependent regulation in a manner beyond what is expected from combining their individual patterns. These results indicate interactions involving distinct cis-elements contribute to the proper integration of pair-rule regulatory information. A model fully accounting for these results proposes that metameric slp1 expression is achieved through the Runt-dependent regulation of interactions between these two pair-rule response elements and the slp1 promoter.
doi:10.1016/j.ydbio.2010.04.026
PMCID: PMC2914134  PMID: 20435028
Runt; Fushi-tarazu; Even-skipped; Odd-paired
23.  Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence 
PLoS Computational Biology  2014;10(3):e1003467.
Modeling a gene's expression from its intergenic locus and trans-regulatory context is a fundamental goal in computational biology. Owing to the distributed nature of cis-regulatory information and the poorly understood mechanisms that integrate such information, gene locus modeling is a more challenging task than modeling individual enhancers. Here we report the first quantitative model of a gene's expression pattern as a function of its locus. We model the expression readout of a locus in two tiers: 1) combinatorial regulation by transcription factors bound to each enhancer is predicted by a thermodynamics-based model and 2) independent contributions from multiple enhancers are linearly combined to fit the gene expression pattern. The model does not require any prior knowledge about enhancers contributing toward a gene's expression. We demonstrate that the model captures the complex multi-domain expression patterns of anterior-posterior patterning genes in the early Drosophila embryo. Altogether, we model the expression patterns of 27 genes; these include several gap genes, pair-rule genes, and anterior, posterior, trunk, and terminal genes. We find that the model-selected enhancers for each gene overlap strongly with its experimentally characterized enhancers. Our findings also suggest the presence of sequence-segments in the locus that would contribute ectopic expression patterns and hence were “shut down” by the model. We applied our model to identify the transcription factors responsible for forming the stripe boundaries of the studied genes. The resulting network of regulatory interactions exhibits a high level of agreement with known regulatory influences on the target genes. Finally, we analyzed whether and why our assumption of enhancer independence was necessary for the genes we studied. We found a deterioration of expression when binding sites in one enhancer were allowed to influence the readout of another enhancer. Thus, interference between enhancer activities was a possible factor necessitating enhancer independence in our model.
Author Summary
Quantitative modeling of gene expression from DNA sequences and regulatory inputs underpin our studies of gene regulation. The existing literature focuses on modeling parts of a gene's expression pattern from its experimentally characterized “enhancers”, which are ∼1 Kbp long sequences, often located in the gene's intergenic region or “locus.” However, a far-reaching goal is to model all aspects of a gene's expression based on the genome sequence, without prior knowledge of enhancers. With this motivation, we have developed a model that maps a gene's locus and cellular context to its expression in that context. Using this model, we study the regulation of 27 genes having complex expression patterns in the Drosophila embryo. Our findings suggest the presence of sequence segments that can irreconcilably distort the gene's expression pattern and thus have to be “shut-down” by the model. We also apply the model to identify the transcription factors forming the stripe boundaries of the studied genes; and our results agree remarkably with experimental findings of decades of work. Finally, we develop a new method to analyze if and why multiple segments influencing a gene's expression need to avoid interaction between themselves.
doi:10.1371/journal.pcbi.1003467
PMCID: PMC3945089  PMID: 24604095
24.  The Intersection of the Extrinsic Hedgehog and WNT/Wingless Signals with the Intrinsic Hox Code Underpins Branching Pattern and Tube Shape Diversity in the Drosophila Airways 
PLoS Genetics  2015;11(1):e1004929.
The tubular networks of the Drosophila respiratory system and our vasculature show distinct branching patterns and tube shapes in different body regions. These local variations are crucial for organ function and organismal fitness. Organotypic patterns and tube geometries in branched networks are typically controlled by variations of extrinsic signaling but the impact of intrinsic factors on branch patterns and shapes is not well explored. Here, we show that the intersection of extrinsic hedgehog(hh) and WNT/wingless (wg) signaling with the tube-intrinsic Hox code of distinct segments specifies the tube pattern and shape of the Drosophila airways. In the cephalic part of the airways, hh signaling induces expression of the transcription factor (TF) knirps (kni) in the anterior dorsal trunk (DTa1). kni represses the expression of another TF spalt major (salm), making DTa1 a narrow and long tube. In DTa branches of more posterior metameres, Bithorax Complex (BX-C) Hox genes autonomously divert hh signaling from inducing kni, thereby allowing DTa branches to develop as salm-dependent thick and short tubes. Moreover, the differential expression of BX-C genes is partly responsible for the anterior-to-posterior gradual increase of the DT tube diameter through regulating the expression level of Salm, a transcriptional target of WNT/wg signaling. Thus, our results highlight how tube intrinsic differential competence can diversify tube morphology without changing availabilities of extrinsic factors.
Author Summary
Tubes are common structural elements of many internal organs, facilitating fluid flow and material exchange. To meet the local needs of diverse tissues, the branching patterns and tube shapes vary regionally. Diametric tapering and specialized branch targeting to the brain represent two common examples of variations with organismal benefits in the Drosophila airways and our vascular system. Several extrinsic signals instruct tube diversifications but the impact of intrinsic factors remains underexplored. Here, we show that the local, tube-intrinsic Hox code instructs the pattern and shape of the dorsal trunk (DT), the main Drosophila airway. In the cephalic part (DT1), where Bithorax Complex (BX-C) Hox genes are not expressed, the extrinsic Hedgehog signal is epistatic to WNT/Wingless signals. Hedgehog instructs anterior DT1 cells to take a long and narrow tube fate targeting the brain. In more posterior metameres, BX-C genes make the extrinsic WNT/Wingless signals epistatic over Hedgehog. There, WNT/Wingless instruct all DT cells to take the thick and short tube fate. Moreover, BX-C genes modulate the outputs of WNT/wingless signaling, making the DT tubes thicker in more posterior metameres. We provide a model for how intrinsic factors modify extrinsic signaling to control regional tube morphologies in a network.
doi:10.1371/journal.pgen.1004929
PMCID: PMC4304712  PMID: 25615601
25.  Interplay between a Wnt-dependent organiser and the Notch segmentation clock regulates posterior development in Periplaneta americana 
Biology Open  2012;2(2):227-237.
Summary
Sequential addition of segments in the posteriorly growing end of the embryo is a developmental mechanism common to many bilaterians. However, posterior growth and patterning in most animals also entails the establishment of a ‘posterior organiser’ that expresses the Caudal and Wnt proteins and has been proposed to be an ancestral feature of animal development. We have studied the functional relationships between the Wnt-driven organiser and the segmentation mechanisms in a basal insect, the cockroach Periplaneta americana. Here, posteriorly-expressed Wnt1 promotes caudal and Delta expression early in development to generate a growth zone from which segments will later bud off. caudal maintains the undifferentiated growth zone by dampening Delta expression, and hence Notch-mediated segmentation occurs just outside the caudal domain. In turn, Delta expression maintains Wnt1, maintaining this posterior gene network until all segments have formed. This feedback between caudal, Wnt and Notch-signalling in regulating growth and segmentation seems conserved in other arthropods, with some aspects found even in vertebrates. Thus our findings not only support an ancestral Wnt posterior organiser, but also impinge on the proposals for a common origin of segmentation in arthropods, annelids and vertebrates.
doi:10.1242/bio.20123699
PMCID: PMC3575657  PMID: 23430316
Caudal; Wnt; Notch; Posterior organiser; Segmentation; Periplaneta americana

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