BIOLOGICAL OVERVIEW

odd-paired appears to be an oddity among the pair-rule transcription factors. During early development of the embryo, odd-paired is not found in a pair-rule, strongly zebra-striped expression pattern, as are other pair-rule genes. Instead, it is transcribed ubiquitously in the central 60% of the embryo. Only later does it assume a banded appearance, in this case, 14 weakly staining zebra stripes. Since all other pair-rule proteins appear in only 7 stripes, OPA is indeed an anomaly. Its classification as a pair-rule gene arises from its mutant phenotype and not its expression pattern (Benedyk, 1994).

Despite its peculiarities, opa functions like other pair-rule genes, and is involved in the induction of wingless into the posterior compartments of parasegments. Because opa's effects are localized, while its expression is not, the positive regulation of wingless must be permissive and not instructive. opa doesn't signal location but simply gives permission. opa appears to act in conjuction with other transcription factors that provide positional signals.

One odd-paired function should be highlighted because it takes place in the mesoderm, rather than the ectoderm. opa is required for the formation of midgut constrictions. It is expressed ubiquitously in segmented regions of both ectoderm and mesoderm. This expression ceases and later reinitiates in restricted portions of the mesoderm. This expression is positively regulated by homeotic genes Antennapedia and abdominal-A, and negatively regulated by Ultrabithorax and decapentaplegic in opa negative areas (Cimbora, 1995).

Runt and Opa cooperate to activate slp1 transcription

A crucial step in generating the segmented body plan in Drosophila is establishing stripes of expression of several key segment-polarity genes, one stripe for each parasegment, in the blastoderm stage embryo. It is well established that these patterns are generated in response to regulation by the transcription factors encoded by the pair-rule segmentation genes. However, the full set of positional cues that drive expression in either the odd- or even-numbered parasegments has not been defined for any of the segment-polarity genes. Among the complications for dissecting the pair-rule to segment-polarity transition are the regulatory interactions between the different pair-rule genes. An ectopic expression system that allows for quantitative manipulation of expression levels was used to probe the role of the primary pair-rule transcription factor Runt in segment-polarity gene regulation. These experiments identify sloppy paired 1 (slp1), most appropriately classified as segment polarity genes, as a gene that is activated and repressed by Runt in a simple combinatorial parasegment-dependent manner. The combination of Runt and Odd-paired (Opa) is both necessary and sufficient for slp1 activation in all somatic blastoderm nuclei that do not express the Fushi tarazu (Ftz) transcription factor (see The pair-rule to segment-polarity transition). By contrast, the specific combination of Runt + Ftz is sufficient for slp1 repression in all blastoderm nuclei. Furthermore Ftz is found to modulate the Runt-dependent regulation of the segment-polarity genes wingless (wg) and engrailed (en). However, in the case of en the combination of Runt + Ftz gives activation. The contrasting responses of different downstream targets to Runt in the presence or absence of Ftz is thus central to the combinatorial logic of the pair-rule to segment-polarity transition. The unique and simple rules for slp1 regulation make this an attractive target for dissecting the molecular mechanisms of Runt-dependent regulation (Swantek, 2004; full text of article).

A somewhat surprising result from these experiments is that slp1 expression in odd-numbered parasegments is lost in opa mutant embryos (see Runt and Opa cooperate to activate slp1 transcription). The importance of Opa is surprising since expression of other segment-polarity genes is reduced, but not eliminated in opa mutants (Benedyk, 1994; Cimbora, 1995). Moreover, Opa is expressed at uniform levels throughout the pre-segmental region of the embryo, and thus does not provide positional information that defines the placement of slp1 stripes relative to other pair-rule transcription factors. The odd-numbered slp1 stripes require Runt, and are interpreted to expand in response to ectopic Runt. The requirement for Opa in this Runt-dependent activation was tested by examining slp1 expression in embryos that have high levels of NGT-driven (NGT stands for nanos-GAL4-tubulin) Runt and that are also mutant for opa. Expression of slp1 within the pre-segmental region is lost in these embryos. This result corroborates the interpretation that the expanded slp1 stripes produced by NGT-driven Runt correspond to the odd-numbered stripes and further confirms the importance of Opa for Runt-dependent activation (Swantek, 2004).

A useful feature of the GAL4 expression system is that expression levels can be varied by changing the strengths of either the GAL4 driver, or the responding UAS transgene. Advantage of this feature was taken to further investigate the relative roles of Runt and Opa in slp1 regulation by generating a co-expression matrix with a panel of different UAS-runt and UAS-opa lines. Increasing the level of Opa in embryos with the same low level of NGT-driven Runt alters slp1 in a manner similar to that obtained by increasing Runt alone. Thus, Opa potentiates Runt-dependent regulation in a concentration-dependent manner. Concentration-dependent effects of Opa are also observed at both intermediate and high levels of NGT-driven Runt. In order to interpret these changes, it is useful to first consider the relatively simple, yet striking response of slp1 to high levels of both Runt and Opa. In these embryos, slp1 is expressed throughout the anterior head region and is nearly uniformly repressed throughout the pre-segmental region of the embryo. The anterior activation is particularly informative since none of the other pair-rule or segment-polarity gene shows this response to Runt and Opa. Thus, anterior activation of slp1 by Runt and Opa occurs in the absence of regulatory inputs from other segmentation genes. It is notable that anterior activation can be triggered either by increasing the level of Runt in embryos with constant intermediate levels of Opa, or by increasing the levels of Opa in embryos with constant intermediate levels of Runt. The observation that Runt and Opa are both obligatory for anterior activation, coupled with this mutual dose-dependent cooperation strongly suggests that these two factors function together in a concentration-dependent complex to activate slp1transcription (Swantek, 2004).

The other notable response to high levels of Runt and Opa is the nearly complete repression of slp1 throughout the presegmental region of the embryo. slp1 and ftz are expressed in complementary patterns in embryos with high uniform levels of Runt. Examination of the response of ftz to the co-expression of Runt and Opa indicates a perfect correlation between the elimination of slp1 and the expansion of ftz. These observations indicate that Opa potentiates the ability of Runt to activate ftz. Moreover, these results strongly suggest that Ftz plays a key role in slp1 repression (Swantek, 2004).

odd-paired regulates decapentaplegic during adult head development

The eye/antennal discs of Drosophila form most of the adult head capsule. The role of the BMP family member decapentaplegic (dpp) in the process of head formation is being analyzed, since a class of cis-regulatory dpp mutations (dpp^s-hc) have been identified that specifically disrupts expression in the lateral peripodial epithelium of eye/antennal discs and is required for ventral head formation. This study describes the recovery of mutations in odd-paired (opa), a zinc finger transcription factor related to the vertebrate Zic family, as dominant enhancers of this dpp head mutation. A single loss-of-function opa allele in combination with a single copy of a dpp^s-hc produces defects in the ventral adult head. Furthermore, postembryonic loss of opa expression alone causes head defects identical to loss of dpp^s-hc/dpp^s-hc, and dpp^hc/+;opa/+ mutant combinations. opa is required for dpp expression in the lateral peripodial epithelium, but not other areas of the eye/antennal disc. Thus a pathway that includes opa and dpp expression in the peripodial epithelium is crucial to the formation of the ventral adult head. Zic proteins and members of the BMP pathway are crucial for vertebrate head development, since mutations in them are associated with midline defects of the head. The interaction of these genes in the morphogenesis of the fruitfly head suggests that the regulation of head formation may be conserved across metazoans (Lee, 2007).

This work demonstrates that opa is an upstream activator of dpp in the peripodial epithelium, and acts in a cell-autonomous fashion. It is not known whether this role is direct, with Opa acting as a transcription factor for dpp, or through other proteins. This ability to activate dpp appears limited to the peripodial epithelium of the eye/antennal disc, since misexpression of Opa in the disc proper does not induce expression. Furthermore, Opa acts only on a dpp reporter that has expression restricted to the peripodial epithelium of the eye/antennal disc. With the exception of antennal defects, loss-of-function clones of opa produce identical head defects to homozygous dpp^s-hc mutants, and ectopic expression of either Dpp or Opa in the peripodial epithelium produces a similar spectrum of misplaced sensory structures. These data suggest that dpp is the major target of opa in the peripodial epithelium (Lee, 2007).

Both opa and dpp are involved in embryonic midgut development, where dpp is a negative regulator of opa in the visceral mesoderm. In addition, BMP2 and BMP4 are negative regulators of Zic proteins in zebrafish, but the exact mechanism of this regulation is unclear. Thus, Zic family proteins are often seen in regulatory networks with BMP proteins, but there does not seem to be a canonical regulatory relationship. These data indicates that during eye/antennal disc development opa exerts a positive effect on peripodial dpp (Lee, 2007).

Both opa and dpp exert their role on ventral head development through expression limited to the peripodial epithelium of the eye/antennal disc. The structures affected in ventral head capsule mutations, such as palps and vibrissae, are reported to arise from the disc proper in the fate map of the eye/antennal disc; thus the effect of Opa-Dpp signal transduction could be to cross epithelial layers, from the peripodial epithelium to the disc proper. Loss of lateral peripodial Dpp expression results in apoptosis in the underlying disc proper, which further suggests a role for peripodial signaling to support disc proper cell viability and morphogenesis. However, when the descendants of peripodial cells are followed by the perdurance of ß-galactosidase expression through metamorphosis, significant contributions of lateral peripodial cells are found in areas of the ventral head where defects are observed in dpp^s-hc or opa mutations, suggesting that the ventral adult head is formed from descendants of both disc proper and peripodial cells. Adult head expression has also been seen with the MS1096-Gal4 driver, of which expression in the eye disc is limited to the lateral and medial peripodial epithelium and margin cells. These data provide further support to the idea that the peripodial epithelium provides more than passive or purely mechanical functions during disc development. The role of the peripodial epithelium in imaginal disc development has begun to receive more attention, and there is evidence that peripodial-specific signaling affects the patterning of the eye, growth control and the fusion of discs at metamorphosis. It now seems likely that in addition to providing such support to cells of the disc proper, peripodial cells contribute directly to the cuticle of the adult head (Lee, 2007).

In mice and humans, Zic genes are associated with holoprosencephaly, a congenital head defect the extreme manifestation of which is cyclopia. In holoprosencephaly there is variable loss or disruption in the development of the ventral forebrain, and midline facial structures. Holoprosencephaly is a common defect in humans, and genes in the TGF-ß and hedgehog pathways are also associated with both the human and mouse condition. Relevant to this work, a significant number of holoprosencephaly cases result from autosomal dominant inheritance, and often, obligate carriers of these autosomal dominant pedigrees are clinically normal. This incomplete penetrance suggests extreme dose sensitivity and the presence of multiple modifying loci. The ability of a genetic screen to recover multiple dominant enhancers of the dpp ventral head defect, including opa, suggests that this may be a model for the kind of digenic inheritance seen with holoprosencephaly. The hedgehog pathway is known to be crucial to adult head development in Drosophila, and this work adds TGF-ß and opa to this process in the fruitfly. It will be of interest to see how many other connections exist between vertebrate and fly head malformations (Lee, 2007).

Evidence for the temporal regulation of insect segmentation by a conserved sequence of transcription factors

Long-germ insects, such as the fruit fly Drosophila melanogaster, pattern their segments simultaneously, whereas short-germ insects, such as the beetle Tribolium castaneum, pattern their segments sequentially, from anterior to posterior. While the two modes of segmentation at first appear quite distinct, much of this difference might simply reflect developmental heterochrony. This study now shows that, in both Drosophila and Tribolium, segment patterning occurs within a common framework of sequential Caudal, Dichaete, and Odd-paired expression (see Comparison of long-germ and short-germ segmentation). In Drosophila these transcription factors are expressed like simple timers within the blastoderm, while in Tribolium they form wavefronts that sweep from anterior to posterior across the germband. In Drosophila, all three are known to regulate pair-rule gene expression and influence the temporal progression of segmentation. It is proposed that these regulatory roles are conserved in short-germ embryos, and that therefore the changing expression profiles of these genes across insects provide a mechanistic explanation for observed differences in the timing of segmentation. In support of this hypothesis it was demonstrated that Odd-paired is essential for segmentation in Tribolium, contrary to previous reports (Clark, 2018).

This study has found that segment patterning in both Drosophila and Tribolium occurs within a conserved framework of sequential Caudal, Dichaete and Odd-paired expression. In the case of Opa, there is also evidence for conserved function. However, although the sequence itself is conserved between the two insects, its spatiotemporal deployment across the embryo is divergent. In Drosophila, the factors are expressed ubiquitously within the main trunk, and each turns on or off almost simultaneously, correlating with the temporal progression of a near simultaneous segmentation process. In Tribolium, their expression domains are staggered in space, with developmentally more advanced anterior regions always subjected to a 'later' regulatory signature than more-posterior tissue. These expression domains retract over the course of germband extension, correlating with the temporal progression of a sequential segmentation process built around a segmentation clock (Clark, 2018).

Pair-rule patterning involves several distinct phases of gene expression, each requiring specific regulatory logic. It is proposed that, in both long-germ and short-germ species, the whole process is orchestrated by a series of key regulators, expressed sequentially over time, three of which are the focus of this paper. By rewiring the regulatory connections between other genes, factors such as Dichaete and Opa allow a small set of pair-rule factors to carry out multiple different roles, each specific to a particular spatiotemporal regulatory context. This kind of control logic makes for a flexible, modular regulatory network, and may therefore turn out to be a hallmark of other complex patterning systems (Clark, 2018).

Having highlighted the significance of these 'timing factors' in this paper, the next steps will be to investigate their precise regulatory roles and modes of action. It will be interesting to dissect how genetic interactions with pair-rule factors are implemented at the molecular level. Dichaete is known to act both as a repressive co-factor and as a transcriptional activator; therefore, a number of different mechanisms are plausible. The Odd-paired protein is also likely to possess both these kinds of regulatory activities (Clark, 2018).

Given the phylogenetic distance between beetles and flies (separated by at least 300 million years), it is expected that the similarities seen between Drosophila and Tribolium segmentation are likely to hold true for other insects, and perhaps for many non-insect arthropods as well. It is proposed that these similarities, which argue for the homology of long-germ and short-germ segmentation processes, result from conserved roles of Cad, Dichaete and Opa in the temporal regulation of pair-rule and segment-polarity gene expression during segment patterning. This hypothesis can be tested by detailed comparative studies in various arthropod model organisms (Clark, 2018).

This study provides evidence that a segmentation role for Opa is conserved between Drosophila and Tribolium; clear segmentation phenotypes have also been found for Cad in Nasonia, and for Dichaete in Bombyx. However, as the Tc-opa experiments reveal, functional manipulations in short-germ insects will need to be designed carefully in order to bypass the early roles of these pleiotropic genes. For example, cad knockdowns cause severe axis truncations in many arthropods, whereas Dichaete knockdown in Tribolium yields mainly empty eggs (Clark, 2018).

It was previously thought that Tc-opa was not required for segmentation, and that the segmentation role of Opa may have been recently acquired, in the lineage leading to Drosophila. However, the current analysis reveals that Tc-opa is indeed a segmentation gene, and also has other important roles, including head patterning and blastoderm formation. Given that a similar developmental profile of opa expression is seen in the millipede Glomeris, and even in the onychophoran Euperipatoides, the segmentation role of Opa may actually be ancient (Clark, 2018).

Head phenotypes following Tc-opa RNAi were unexpected, but both the blastoderm expression pattern and cuticle phenotypes that were observed are strikingly similar to those reported for Tc-otd and Tc-ems (Tribolium orthologues of the Drosophila head 'gap' genes orthodenticle and empty spiracles), suggesting that the three genes function together in a gene network that controls early head patterning. This function of Tc-opa might be homologous to the head patterning role for Opa discovered in the spider Parasteatoda, where it interacts with both Otd and Hedgehog (Hh) expression. Opa/Zic is known to modulate Hh signalling, and a role for Hh in head patterning appears to be conserved across arthropods, including Tribolium (Clark, 2018).

Finally, Opa/Zic is also known to modulate Wnt signalling. In chordates, Zic expression tends to overlap with sites of Hh and/or Wnt signalling, suggesting that one of its key roles in development is to ensure cells respond appropriately to these signals. The expression domains of Tc-opa that were observed in Tribolium (e.g. in the head, in the SAZ and between parasegment boundaries) accord well with this idea (Clark, 2018).

Similar embryonic expression patterns of Cad, Dichaete and Opa orthologues are observed in other bilaterian clades, including vertebrates. Cdx genes are expressed in the posterior of vertebrate embryos, where they play crucial roles in axial extension and Hox gene regulation. Sox2 (a Dichaete orthologue) has conserved expression in the nervous system, but is also expressed in a posterior domain, where it is a key determinant of neuromesodermal progenitor (posterior stem cell) fate. Finally, Zic2 and Zic3 (Opa orthologues) are expressed in presomitic mesoderm and nascent somites, and have been functionally implicated in somitogenesis and convergent extension. All three factors thus have important functions in posterior elongation, roles that may well be conserved across Bilateria (Clark, 2018).

In Tribolium, all three factors may be integrated into an ancient gene regulatory network downstream of posterior Wnt signalling, which generates their sequential expression and helps regulate posterior proliferation and/or differentiation. The mutually exclusive patterns of Tc-wg and Tc-Dichaete in the posterior germband are particularly suggestive: Wnt signalling and Sox gene expression are known to interact in many developmental contexts and these interactions may form parts of temporal cascades) (Clark, 2018).

The following outline is suggested as a plausible scenario for the evolution of arthropod segmentation; In non-segmented bilaterian ancestors of the arthropods, Cad, Dichaete and Opa were expressed broadly similarly to how they are expressed in Tribolium today, mediating conserved roles in posterior elongation, while gap and pair-rule genes may have had functions in the nervous system. At some point, segmentation genes came under the regulatory control of these factors, which provided a pre-existing source of spatiotemporal information in the developing embryo. Pair-rule genes began oscillating in the posterior, perhaps under the control of Cad and/or Dichaete, while the posteriorly retracting expression boundaries of the timing factors provided smooth wavefronts that effectively translated these oscillations into periodic patterning of the AP axis, analogous to the roles of the opposing retinoic acid and FGF gradients in vertebrate somitogenesis. Much later, in certain lineages of holometabolous insects, the transition to long-germ segmentation occurred. This would have involved two main modifications of the short-germ segmentation process: (1) changes to the expression of the timing factors, away from the situation seen in Tribolium, and towards the situation seen in Drosophila, causing a heterochronic shift in the deployment of the segmentation machinery from SAZ to blastoderm; and (2) recruitment of gap genes to pattern pair-rule stripes, via the ad hoc evolution of stripe-specific elements (Clark, 2018).

The appeal of this model is that the co-option of existing developmental features at each stage reduces the number of regulatory changes required to evolve de novo, facilitating the evolutionary process. In this scenario, arthropod segmentation would not be homologous to segmentation in other phyla, but would probably have been fashioned from common parts (Clark, 2018).

The transcription factor odd-paired regulates temporal identity in transit-amplifying neural progenitors via an incoherent feed-forward loop

Neural progenitors undergo temporal patterning to generate diverse neurons in a chronological order. This process is well-studied in the developing Drosophila brain and conserved in mammals. During larval stages, intermediate neural progenitors (INPs) serially express Dichaete (D), grainyhead (Grh) and eyeless (Ey/Pax6), but how the transitions are regulated is not precisely understood. In this study a method was developed to isolate transcriptomes of INPs in their distinct temporal states to identify a complete set of temporal patterning factors. This analysis identifies odd-paired (opa), as a key regulator of temporal patterning. Temporal patterning is initiated when the SWI/SNF complex component Osa induces D and its repressor Opa at the same time but with distinct kinetics. Then, high Opa levels repress D to allow Grh transcription and progress to the next temporal state. It is proposed that Osa and its target genes opa and D form an incoherent feedforward loop (FFL) and a new mechanism allowing the successive expression of temporal identities (Abdusselamoglu, 2019).

Temporal patterning is a phenomenon where NSCs alter the fate of their progeny chronologically. Understanding how temporal patterning is regulated is crucial to understanding how the cellular complexity of the brain develops. This study presents a novel, FACS-based approach that enabled isolation of distinct temporal states of neural progenitors with very high purity from Drosophila larvae. This allowed a study the transitions between different temporal identity states. odd-paired (opa), a transcription factor that is required for INP temporal patterning, was identified. By studying the role of this factor in temporal patterning, a novel model is proposed for the regulation of temporal patterning in Drosophila neural stem cells (Abdusselamoglu, 2019).

Two different roles are established of the SWI/SNF complex subunit, Osa, in regulating INP temporal patterning. Initially, Osa initiates temporal patterning by activating the transcription factor D. Subsequently, Osa regulates the progression of temporal patterning by activating opa and ham, which in turn downregulate D and Grh, respectively. The concerted, but complementary action of opa and ham ensures temporal identity progression by promoting the transition between temporal stages. For instance, opa regulates the transition from D to Grh, while ham regulates the transition from Grh to Ey. It is proposed that opa achieves this by repressing D and activating grh, as indicated by the lack of temporal patterning in D and opa-depleted INPs. Loss of opa or ham causes INPs to lose their temporal identity and overproliferate. Moreover, it is proposed that D and opa activate Grh expression against the presence of ham, which represses Grh expression. As D and opa levels decrease as INPs age and become Grh positive, ham is capable of repressing Grh later on in temporal patterning. This explains how opa and ham act only during specific stages even though they are expressed throughout the entire lineage (Abdusselamoglu, 2019).

An open question pertains to the fact that the double knock-down of opa and ham, as well as that of D and opa, failed to recapitulate the Osa phenotype. Even though opa and ham RNAi caused massive overproliferation in type II lineages, no Dpn+ Ase- ectopic NB-like cells (as occurs in Osa mutant clones) were detected. It is proposed that this is caused by D expression, which is still induced even upon opa/ham double knockdown, but not upon Osa knock-down, where D expression fails to be initiated. Thus, the initiation of the first temporal identity state may block the reversion of INPs to a NB-state. In the future, it will be important to understand the exact mechanisms of how opa regulates temporal patterning (Abdusselamoglu, 2019).

This study further demonstrates that Osa initiates D expression earlier than opa expression. Osa is a subunit of SWI/SNF chromatin remodeling complex, and it guides the complex to specific loci throughout the genome, such as the TSS of both D and opa. The differences in timing of D and opa expression may be explained by separate factors involved in their activation. Previous work suggests that the transcription factor earmuff may activate . However, it remains unknown which factor activates opa expression. One possibility is that the cell cycle activates opa, since its expression begins in mINPs, a dividing cell unlike imINPs, which are in cell cycle arrest (Abdusselamoglu, 2019).

It is proposed that balanced expression levels of D and opa regulate the timing of transitions between temporal identity states. Indeed, Osa initiates D and opa, the repressor of D, at slightly different times, which could allow a time window for D to be expressed, perform its function, then become repressed again by opa. Deregulating this pattern, for example by overexpressing opa in the earliest INP stage, results in a false start of temporal patterning and premature differentiation. This elegant set of genetic interactions resembles that of an incoherent feedforward loop (FFL). In such a network, pathways have opposing roles. For instance, Osa promotes both the expression and repression of D. Similar examples can be observed in other organisms, such as in the galactose network of E. coli, where the transcriptional activator CRP activates galS and galE, while galS also represses galE. In Drosophila SOP determination, miR-7, together with Atonal also forms an incoherent FFL. Furthermore, mammals apply a similar mechanism in the c-Myc/E2F1 regulatory system (Abdusselamoglu, 2019).

The vertebrate homologues of opa consist of the Zinc-finger protein of the cerebellum (ZIC) family, which are suggested to regulate the transcriptional activity of target genes, and to have a role in CNS development. In mice, during embryonic cortical development, ZIC family proteins regulate the proliferation of meningeal cells, which are required for normal cortical development. In addition, another member of the ZIC family, Zic1, is a Brn2 target, which itself controls the transition from early-to-mid neurogenesis in the mouse cortex. Along with these lines, it has been shown that ZIC family is important in brain development in zebrafish. Furthermore, the role of ZIC has been implicated in variety of brain malformations and/or diseases. These data provide mere glimpses into the roles of ZIC family proteins in neuronal fate decisions in mammals, and this study offers an important entry point to start understanding these remarkable proteins (Abdusselamoglu, 2019).

These findings provide a novel regulatory network model controlling temporal patterning, which may occur in all metazoans, including humans. In contrast to existing cascade models, this study instead shows that temporal patterning is a highly coordinated ensemble that allows regulation on additional levels than was previously appreciated to ensure a perfectly balanced generation of different neuron/glial cell types. Together, these results demonstrate that Drosophila is a powerful system to dissect the genetic mechanisms underlying the temporal patterning of neural stem cells and how the disruption of such mechanisms impacts brain development and behavior (Abdusselamoglu, 2019).

GENE STRUCTURE

date revised: 20 January 2007

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