Border-cell migration requires integration of spatial and temporal signals by the BTB protein Abrupt

During development, elaborate patterns of cell differentiation and movement must occur in the correct locations and at the proper times. Developmental timing has been studied less than spatial pattern formation, and the mechanisms integrating the two are poorly understood. Border-cell migration in the Drosophila ovary occurs specifically at stage 9. Timing of the migration is regulated by the steroid hormone ecdysone, whereas spatial patterning of the migratory population requires localized activity of the JAK-STAT pathway. Ecdysone signalling is patterned spatially as well as temporally, although the mechanisms are not well understood. In stage 9 egg chambers, ecdysone signalling is highest in anterior follicle cells including the border cells. abrupt was identified as a repressor of ecdysone signalling and border-cell migration. Abrupt protein is normally lost from border-cell nuclei during stage 9, in response to JAK-STAT activity. This contributes to the spatial pattern of the ecdysone response. Abrupt attenuates ecdysone signalling by means of a direct interaction with the basic helix-loop-helix (bHLH) domain of the P160 ecdysone receptor coactivator Taiman (Tai). Taken together, these findings provide a molecular mechanism by which spatial and temporal cues are integrated (Jang, 2009).

Embryonic development unfolds as a series of changes in gene expression that are regulated in both space and time. The fundamental mechanisms of spatial patterning have been established. Temporal patterns of gene expression can be regulated globally by circulating hormones or locally by the sequential actions of transcription factors on one another. What remains to be elucidated are the mechanisms by which spatial and temporal patterns are integrated. This study identifies Abrupt as playing such a part in border cells (Jang, 2009).

The following model is proposed for the molecular integration of spatial and temporal control of border cell migration. Early in stage 9 the ecdysone titer begins to rise. Although the precise pattern in which it is produced is not known, it may be uniform. At this stage, EcRB1 expression is enriched in anterior follicle cells, leading to an enhanced ecdysone response in these cells. In response to ecdysone signaling, the levels of Abrupt protein begin to fall in anterior follicle cells, leading to a feedback amplification of the ecdysone response in those cells, further reduction in Abrupt protein levels and thus a gradually decreasing level of nuclear Abrupt throughout stage 9. Since the asymmetry in EcRB1 expression is transient, this feedback mechanism is necessary to maintain the spatially localized effect in the absence of the initiating event. Abrupt protein levels also decrease in response to JAK/STAT signaling, which is sustained and highest in border cells (Jang, 2009).

The gradual decrease in the concentration of Abrupt in border cell nuclei due to the combined action of ecdysone signaling and JAK/STAT leads to a gradual increase in ecdysone signaling throughout stage 9, producing a temporal gradient. The gradual nature of the effect may serve as a buffer against any excessively rapid increase in the ecdysone concentration that might occur. As was shown in Tai(βB) overexpression, very high levels of ecdysone signaling are not compatible with border cell migration and may even serve as a stop signal since the highest level of ecdysone reporter expression occur at stage 10, which is the stage at which border cells stop migrating (Jang, 2009).

Two other BTB domain proteins that function in developmental timing are Chinmo (Chronologically inappropriate morphogenesis) and BrC (Broad Complex). These factors contribute to the temporal sequence of neuronal cell fates during postembryonic development. Early neuronal precursors express high levels of Chinmo, which subsequently decay by a post-transcriptional mechanism. Loss of Chinmo from early neuroblasts converts their progeny to later identities whereas over-expression of Chinmo has the opposite effect. In the developing larval CNS, early born neurons express higher levels of Chinmo and later born cells express BrC in a largely complementary pattern. Thus temporal regulation may be a general property of proteins containing both BTB and Zn2+ finger domains (Jang, 2009).

Could the three temporal control mechanisms that have been studied largely separately, actually represent a single unified mechanism? The work presented here demonstrates that Abrupt protein levels respond to ecdysone signaling and in turn affect the ecdysone response in the Drosophila ovary. Very recently, Abrupt has also been shown to be a direct target for the let-7 microRNA in larval muscle cells. Drosophila let-7 is homologous to one of the original miRNAs identified as a heterochronic gene in C. elegans. Drosophila let-7 is widely expressed in ecdysone-responsive tissues including ovaries and like ecdysone, is required for metamorphosis and for female (not male) fertility. Drosophila let-7 expression may require EcR or ecdysone and let-7 may function in parallel pathways to regulate developmental timing. The border cells now represent a well-developed model in which spatial and temporal control can be examined at the single cell level so that precise molecular mechanisms can be unraveled. Further investigation of this model system could help determine whether hormone, microRNA and BTB domain transcription factors are all part of one unified developmental timing pathway or function in parallel (Jang, 2009).

Heterodimer of two bHLH-PAS proteins mediates juvenile hormone-induced gene expression

Juvenile hormone (JH) plays crucial roles in many aspects of insect life. The Methoprene-tolerant (Met) gene product, a member of the bHLH-PAS family of transcriptional regulators, has been demonstrated to be a key component of the JH signaling pathway. However, the molecular function of Met in JH-induced signal transduction and gene regulation remains to be fully elucidated. This study, analyzing mosquito Met, shows that a transcriptional coactivator of the ecdysteroid receptor complex, FISC (Drosophila homolog: Taiman), acts as a functional partner of Met in mediating JH-induced gene expression. Mosquito Met and FISC appear to use their PAS domains to form a dimer only in the presence of JH or JH analogs. In newly emerged adult female mosquitoes, expression of some JH responsive genes is considerably dampened when Met or FISC is depleted by RNAi. Met and FISC are found to be associated with the promoter of the early trypsin gene (AaET) when transcription of this gene is activated by JH. A juvenile hormone response element (JHRE) has been identified in the AaET upstream regulatory region and is bound in vitro by the Met-FISC complex present in the nuclear protein extracts of previtellogenic adult female mosquitoes. In addition, the Drosophila homologs of Met and FISC (Taiman) can also use this mosquito JHRE to activate gene transcription in response to JH in a cell transfection assay. Together, the evidence indicates that Met and FISC form a functional complex on the JHRE in the presence of JH and directly activate transcription of JH target genes (Li, 2011).

Genetic studies have shown that Met is required for proper expression of JH target genes in fruit flies, red flour beetles, and mosquitoes. Although the protein structure of Met suggests that it may act as a JH-activated transcriptional regulator, the binding of Met to JH-responsive promoters has not been definitively demonstrated so far. In this study, a chromatin immunoprecipitation experiment indicated that Met was indeed associated with the early trypsin promoter when this gene was activated by endogenous juvenile hormone in the newly emerged adult female mosquitoes. This is a unique demonstration of Met directly regulating a JH target gene (Li, 2011).

To elucidate the molecular roles of Met in JH signaling, a number of proteins have been tested in vitro or in the cultured insect cells for their abilities to bind Met. The protein interactions with Met were largely independent of the presence of JH, or even repressed by JH. Using a library screening approach, a mosquito bHLH-PAS protein (FISC) was identified that binds to Met in a JH-dependent manner. EMSA and ChIP experiments have demonstrated that the Met-FISC complex forms in vivo and binds to a JH-regulated promoter in previtellogenic mosquitoes only in the presence of high titers of juvenile hormone. This observation is consistent with the RNAi results showing that both Met and FISC are required in adult mosquitoes for activation of JH target genes, such as AaET and AaKr-h1. The GBD-Met fusion (without the GAD-FISC fusion) activated the UASx4-188-cc-Luc reporter gene after the JH treatment. This activation also relied on the endogenous Taiman protein in the L57 cells; the JH induction was severely dampened when Taiman was depleted by RNAi. Formation of the Met-FISC complex thus constitutes a key step in signal transduction of juvenile hormone. It is also worth noting that not all of the JH target genes are affected by RNAi knockdown of Met or FISC, implying that JH might act through several distinct pathways even in a single tissue at a particular developmental stage (Li, 2011).

Transient transfection and gel shift assays indicated that Met-FISC activated the AaET promoter by binding to the JHRE. It is currently under investigation whether the two proteins are directly binding to the JHRE or are recruited to the JHRE via protein interaction with other transcription factors. Because of the relative large sizes of the two proteins, it is difficult to obtain full-length and functional recombinant Met and FISC proteins. EMSA experiments using in vitro-synthesized proteins turned out to be problematic, because both rabbit reticulocyte lysate and wheat germ extract displayed high background binding to the labeled JHRE. A preliminary study showed that the JH-induced transcriptional activation by Met-FISC was completely abolished in cell transfection assays if the DNA binding domain (bHLH region) of either Met or FISC was truncated. However, the possibility cannot be ruled out that the bHLH regions are also required for interactions with other proteins (Li, 2011).

A distal regulatory region of AaET was also shown to be indispensable for JH-dependent activation of the AaET promoter. Intriguingly, when four copies of JHRE were placed upstream of the minimal promoter (TATA box) of AaET, the JHRE seemed to be sufficient for the Met-FISC mediated JH activation. This discrepancy implies that regulation of JH target genes is more sophisticated than the binding of Met-FISC to JHRE. More studies are needed to elucidate the underlying molecular mechanisms (Li, 2011).

In vitro experiments have shown that Met can bind to both EcR and USP, two components of the ecdysteroid receptor. This study found that FISC, a coactivator of the EcR/USP, also binds to Met and plays an important role in juvenile hormone signaling. Whether these protein interactions are involved in the crosstalk of ecdysone and JH signaling is awaiting further experimental evidence. Because the binding of FISC to EcR/USP and Met relies on the presence of 20-hydroxyecdysone and juvenile hormone respectively, the shuffling of FISC between the two signaling pathways may account for the antagonistic actions of these two hormones (Li, 2011).

A sequence similar to the AaET JHRE is also found in the promoter region of AaJHA15, another JH-regulated gene in adult female mosquitoes. The common motif 2 discovered in a group of JH-activated Drosophila promoters also shares high sequence similarity with the AaET JHRE, suggesting an evolutionarily conserved mechanism underneath the JH-induced transcriptional activation. Indeed, the Drosophila Met and Taiman activated the 4×JHRE-luc reporter gene in a JH-dependent manner. Although DmMet-AaFISC appeared comparable to DmMet-DmTAI in mediating JH-induced gene expression, AaMet-DmTAI was completely unable to activate expression of the reporter gene after JH treatment. This observation suggests that the intricate protein interactions between Met and FISC/TAI determine the affinity of the dimers to the JHRE and/or their ability to activate transcription of the JH target genes (Li, 2011).

Unlike mosquitoes, two Met-like genes (Met and gce) exist in fruit flies. Combination of gce and Taiman also led to considerable activation of the reporter gene in response to JH. This observation is in line with a recent report showing that gce can partially substitute for Met in vivo (Baumann, 2010). It would be interesting to test next whether Met-TAI and gce-TAI preferentially bind to distinct JH responsive promoters in vivo (Li, 2011).


Antibodies were raised against two different regions of the predicted protein, the PASB domain and the LXXLL domain. Both antibodies stain follicle cells in the Drosophila ovary. Nuclear staining was observed in all of the follicle cells, including the border cells; however, much less protein is detected in the nurse cells. Widespread expression is also detected in embryos. The nuclei of tai homozygous mutant cells do not react with the antibody against Tai, though the nuclei are present, as detected by DAPI staining. Tai expression is unchanged in slbo mutant egg chambers, indicating that tai is not a downstream target of slbo (Bai, 2000).

Ecdysteroids affect Drosophila ovarian stem cell niche formation and early germline differentiation

Steroid hormones are required in Drosophila for progression of oogenesis during late stages of egg maturation. This study shows that ecdysteroids regulate progression through the early steps of germ cell lineage. Upon ecdysone signalling deficit germline stem cell progeny delay switching on a differentiation programme. This differentiation impediment is associated with reduced TGF-β signalling in the germline and increased levels of cell adhesion complexes and cytoskeletal proteins in somatic escort cells. A co-activator of the ecdysone receptor, Taiman is the spatially restricted regulator of the ecdysone signalling pathway in soma. Additionally, when ecdysone signalling is perturbed during the process of somatic stem cell niche establishment enlarged functional niches able to host additional stem cells are formed (König, 2011).

This study shows that in Drosophila ecdysone signalling regulates differentiation of a GSC daughter and modulates ovarian stem cell niche size. The delay in GSC progeny differentiation correlates with reduced expression levels of TGF-β pathway components. Based on expression patterns it appears that germarial somatic cells, niche and ECs are the critical sites of ecdysteroid action and a co-activator of ecdysone receptor, Taiman is the spatially restricted regulator of ecdysone signalling in soma. During adulthood the ecdysone pathway has a specific role in EC differentiation and soma-germline cell contact establishment. In addition, during development the ecdysone signalling pathway has a role in somatic niche formation (König, 2011).

Ecdysteroids in general control major developmental transformations such as metamorphosis and morphogenesis in Drosophila. Different tissues and even different cell types within the same tissue respond to this broad signalling in a specific fashion and in a timely manner. In the developing Drosophila ovary steroid hormone receptors are expressed in a well-timed mode, high levels coinciding with proliferative and immature stages and low levels preceding reduced DNA replication and differentiation. Mutations in ecdysone pathway components affect ovarian morphogenesis, including heterochronic delay or acceleration in the onset of terminal filament differentiation. During the niche establishment the levels of both ecdysone receptors, EcR and USP are greatly downregulated in anterior somatic cells that will contribute to the niche per se. This study shows that perturbation of ecdysone signalling in pre-adult ovarian soma leads to the formation of enlarged niches. The specific response to systemic hormonal signalling in niche precursors is achieved by a specific function of the ecdysone receptor co-activator Taiman. When timely regulation of ecdysone signalling does not occur, more cells are recruited to become niche cells resulting in enlarged niches that are capable to host more stem cells. These data first show that ecdysone steroid hormonal signalling regulates the formation of the adult stem cell niche and suggest that a developmental tuning of ecdysone signalling controls the number of anterior somatic cells that will differentiate into cap cells (König, 2011).

It is logical that stem cell division and germline differentiation are regulated by some systemic signalling depending on the general state of the organism, which depends on age, nutrition, environmental conditions and so on. Hormones are great candidates for this type of regulation as they act in a paracrine fashion and their levels are changing in response to ever-changing external and internal conditions. Steroid binding to nuclear receptors in vertebrates triggers a conformational switch accompanied by increased histone acetylation that permits transcriptional co-activators binding and the transcription initiation complex assembly. In Drosophila, the trithorax-related protein, a histone H3 methyltransferase that like Taiman belongs to the p160 class of co-activators, and an ISWI-containing ATP-dependent chromatin remodelling complex (NURF), that regulates transcription by catalysing nucleosome sliding, both bind EcR in an ecdysone-dependent manner, showing that chromatin modifications can mediate response to this general signalling. Transcriptional regulation has a key role in GSC maintenance and differentiation, for example, the TGF-β ligand Dpp secreted by niche cells induces phosphorylation of the transcription factor Mad in GSCs that in turn suppresses transcription of the differentiation factor Bam. In addition, it has been shown recently that in Drosophila adult GSC ecdysone modulates the strength of TGF-β signalling through a functional interaction with the chromatin remodelling factors ISWI and Nurf301, a subunit of the ISWI-containing NURF chromatin remodelling complex (Ables, 2010). Therefore, it is plausible that ecdysone regulates Mad expression cell autonomously via chromatin modifications. Since pMad directly suppresses a differentiation factor Bam, it is expected that Bam would be expressed in pMad-negative cells. Interestingly, the findings show that ecdysone deficit decreases amounts of phosphorylated Mad in GSCs and also cell non-autonomously suppresses Bam in SSCs. As SSCs that express neither pMad nor Bam are accumulated when the ecdysone pathway is perturbed it suggests that there should be an alternative mechanism of Bam regulation. Even though eventually this still can be done on the level of chromatin modification, the data suggest that the origin of this soma-generated signal may be associated with cell adhesion protein levels. Further understanding of the nature of this signalling is of a great interest (König, 2011).

The progression of oogenesis within the germarium requires cooperation between two stem cell types, germline and somatic (escort) stem cells. In Drosophila, reciprocal signals between germline and escort (in female) or somatic cyst (in male) cells can inhibit reversion to the stem cell state and restrict germ cell proliferation and cyst growth. Therefore, the non-autonomous ecdysone effect can be explained by the necessity of two stem cell types that share the same niche (GSC and ESC) to coordinate their division and progeny differentiation. This coordination is most likely achieved via adhesive cues, as disruption of ecdysone signalling affects turnover of adhesion complexes and cytoskeletal proteins in somatic ECs: mutant cells exhibited abnormal accumulation of DE-Cadherin, β-catenin/Armadillo and Adducin (König, 2011).

Cell adhesion has a crucial role in Drosophila stem cells; GSCs are recruited to and maintained in their niches via cell adhesion. Two major components of this adhesion process, DE-Cadherin and Armadillo/β-catenin, accumulate at high levels in the junctions between GSCs and niche cells, while in the developing cystoblasts and escort cells levels of these proteins are strongly reduced. Levels of DE-Cadherin in GSCs are regulated by various signals, for example, nutrition activation of insulin signalling or chemokine activation of STAT, and this study shows that in ESCs it is regulated by steroid hormone signalling. Possibly, these two stem cell types respond to different signals but then differentiation of their progeny is synchronised via cell contacts. While hormones, growth factors and cytokines certainly manage stem cell maintenance and differentiation, the evidence also reveals that the responses to hormonal stimuli are strongly modified by adhesive cues (König, 2011).

Specificity to endocrine signalling can be achieved via availability of co-factors in the targeted tissue. Tai is a spatially restricted co-factor that cooperates with the EcR/USP nuclear receptor complex to define appropriate responses to globally available hormonal signals. Tai-positive regulation of ecdysone signalling can be alleviated by Abrupt via direct binding of these two proteins that prevents Tai association with EcR/USP (Jang, 2009). Abrupt has been shown to be downregulated by JAK/STAT signalling (Jang, 2009). Interestingly, JAK/STAT signalling also has a critical role in ovarian niche function and controls the morphology and proliferation of ESCs as well as GSCs. JAK/STAT signalling may interact with ecdysone pathway components in ECs to further modulate cell type-specific responses to global endocrine signalling. A combination of regulated by different signalling pathway factors that are also spatially and timely restricted builds a network that ensures the specificity of systemic signalling (König, 2011).

Knowledge of how steroids regulate stem cells and their niche has a great potential for stem cell and regenerative medicine. The current findings open the way for a detailed analysis of a role for steroid hormones in niche development and regulation of germline differentiation via adjacent soma (König, 2011).

Effects of Mutation

The border cells of the Drosophila ovary undergo a well-defined and developmentally regulated cell migration. Two signals control where and when the cells migrate. The steroid hormone ecdysone, acting through its receptor and a coactivator known as Taiman, contributes to regulating the timing of border cell migration. PVF1, a growth factor related to platelet-derived growth factor and vascular-endothelial growth factor, contributes to guiding the border cells to the oocyte. To probe the mechanisms controlling border cell migration, a screen was performed for genes that exhibit dominant genetic interactions with taiman. Fourteen genomic regions were identified that interact with taiman. Within one region, Pvf1 was identified as the gene responsible for the interaction. Signaling by PVF1 has been proposed to guide the border cells to their proper target, but ectopic PVF1 has not been tested for its ability to redirect the border cells. The ability of PVF1 (as well as other factors such as Gurken) to guide the border cells to new targets was tested. Ectopic expression of PVF1 is sufficient to redirect border cells in some egg chambers but the other factors tested are not. These data suggest that the guidance of border cell migration is robust and that there are likely to be additional factors that contribute to long-range guidance of these cells. In addition, taiman and Pvf1 regulate the dynamic localization of E-cadherin in the border cells, possibly accounting for the interaction between these two pathways (McDonald, 2003).

The interaction of tai with Pvf1 appears to be specific because tai does not interact with either loss-of-function mutations or deficiencies that remove other genes known to regulate border cell migration, such as slbo or shotgun/DE-cadherin. Mutations in slbo or shotgun reduce DE-cadherin levels in the border cells, so tai does not interact with every gene that regulates DE-cadherin, possibly because tai regulates the distribution rather than the levels of DE-cadherin in the border cells. Identification of Pvf1 indicates that this screen provides a useful approach for identifying additional loci that affect border cell migration in general and regulate turnover of adhesion in particular (McDonald, 2003).

The genetic interaction between Pvf1 and tai indicates that the regulation of border cell migration timing and guidance might be linked. What is the nature of the interaction between tai and Pvf1 during border cell migration? Ecdysone signaling does not regulate PVF1 or PVR expression nor does Pvf1 regulate TAI expression, but the ecdysone and Pvf1 pathways both affect the distribution of DE-cadherin and Arm. A model is favored whereby tai and Pvf1 interact because they both regulate adhesion complex localization or turnover. The tai and Pvf1 genes could act independently to regulate cadherin-dynamics. Alternatively, tai and Pvf1 might function in a common pathway. TAI and PVR both function autonomously in the border cells, although they are unlikely to bind directly to each other because TAI localizes to the nucleus and PVR is a receptor tyrosine kinase localized to the membrane. One possibility is that PVR activates (or represses) the function of a protein whose expression is dependent on TAI, and that this protein in turn regulates cadherin dynamics in the border cells. Tyrosine phosphorylation of ß-catenin, the Arm homolog, causes destabilization of adhesion complexes in other cell types, so perhaps PVR activity destabilizes E-cadherin/Armadillo complexes specifically in the border cells. Identification of additional genes identified in this screen, in particular those that affect adhesion turnover in border cells, should help clarify the biochemical relationship between TAI and PVF1 (McDonald, 2003).

Ecdysone receptor (EcR) suppresses lipid accumulation in the Drosophila fat body via transcription control

Lipid metabolism drastically changes in response to the environmental factors in metazoans. Lipid is accumulated at the food rich condition, while mobilized in adipocyte tissue in starvation. Such lipid mobilization is also evident during the pupation of the insects. Pupation is induced by metamorphosis hormone, ecdysone via ecdysone receptor (EcR) with lipid mobilization, however, the molecular link of the EcR-mediated signal to the lipid mobilization remains elusive. To address this issue, EcR was genetically knocked-down selectively in 3rd instar larva fat body of Drosophila, corresponding to the adipocyte tissues in mammalians, that contains adipocyte-like cells. In this mutant, lipid accumulation was increased in the fat body. Lipid accumulation was also increased when knocked-down of taiman, which served as the EcR co-activator. Two lipid metabolism regulatory factor, E75B and adipose (adp) as well as cell growth factor, dMyc, were found as EcR target genes in the adipocyte-like cells, and consistently knock-down of these EcR target genes brought phenotypes in lipid accumulation supporting EcR function. These findings suggest that EcR-mediated ecdysone signal is significant in lipid metabolism in insects (Kamoshida, 2012).


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taiman: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 15 December 2012

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