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Institute
- Theodor-Boveri-Institut für Biowissenschaften (19) (remove)
Background: According to the classical model of Macevicz and Oster, annual eusocial insects should show a clear dichotomous "bang-bang" strategy of resource allocation; colony fitness is maximised when a period of pure colony growth (exclusive production of workers) is followed by a single reproductive period characterised by the exclusive production of sexuals. However, in several species graded investment strategies with a simultaneous production of workers and sexuals have been observed. Such deviations from the "bang-bang" strategy are usually interpreted as an adaptive (bet-hedging) response to environmental fluctuations such as variation in season length or food availability. To generate predictions about the optimal investment pattern of insect colonies in fluctuating environments, we slightly modified Macevicz and Oster's classical model of annual colony dynamics and used a dynamic programming approach nested into a recurrence procedure for the solution of the stochastic optimal control problem. Results: 1) The optimal switching time between pure colony growth and the exclusive production of sexuals decreases with increasing environmental variance. 2) Yet, for reasonable levels of environmental fluctuations no deviation from the typical bang-bang strategy is predicted. 3) Model calculations for the halictid bee Lasioglossum malachurum reveal that bet-hedging is not likely to be the reason for the graded allocation into sexuals versus workers observed in this species. 4) When environmental variance reaches a critical level our model predicts an abrupt change from dichotomous behaviour to graded allocation strategies, but the transition between colony growth and production of sexuals is not necessarily monotonic. Both, the critical level of environmental variance as well as the characteristic pattern of resource allocation strongly depend on the type of function used to describe environmental fluctuations. Conclusion: Up to now bet-hedging as an evolutionary response to variation in season length has been the main argument to explain field observations of graded resource allocation in annual eusocial insect species. However, our model shows that the effect of moderate fluctuations of environmental conditions does not select for deviation from the classical bang-bang strategy and that the evolution of graded allocation strategies can be triggered only by extreme fluctuations. Detailed quantitative observations on resource allocation in eusocial insects are needed to analyse the relevance of alternative explanations, e.g. logistic colony growth or reproductive conflict between queen and workers, for the evolution of graded allocation strategies.
Caterpillars of the butterfly Maculinea rebeli develop as parasites inside ant colonies. In intensively studied French populations, about 25% of caterpillars mature within 1 year (fast-developing larvae [FDL]) and the others after 2 years (slow-developing larvae [SDL]); all available evidence indicates that this ratio is under the control of egg-laying females. We present an analytical model to predict the evolutionarily stable fraction of FDL (pESS). The model accounts for added winter mortality of SDL, general and kin competition among caterpillars, a competitive advantage of SDL over newly entering FDL (priority effect), and the avoidance of renewed infection of ant nests by butterflies in the coming season (segregation). We come to the following conclusions: (1) all factors listed above can promote the evolution of delayed development; (2) kin competition and segregation stabilize pESS near 0.5; and (3) a priority effect is the only mechanism potentially selecting for. However, given the empirical data, pESS is predicted to fall closer to 0.5 than to the 0.25 that has been observed. In this particular system, bet hedging cannot explain why more than 50% of larvae postpone growth. Presumably, other fitness benefits for SDL, for example, higher fertility or longevity, also contribute to the evolution of delayed development. The model presented here may be of general applicability for systems where maturing individuals compete in small subgroups.
The live sciences currently undergo a paradigm shift to computer aided discoveries. Discoveries in the live sciences were historically made by either direct observation or as a result of chemical assays. Today we see a growing shift toward computer aided analysis and visualization. This gradual process happens in microscopy. Multidimensional laser scanning microscopy can acquire very complex multichannel data from fixed or live specimen. New probes such as visible fluorescent proteins let us observe the expression of genes and track protein localization. Ion sensitive dyes change intensity with the concentration of ions in the cell. The laser scanning confocal allows us to record these processes in three dimensions over time. This work demonstrates the application of software analysis to multidimensional microscopy data. We introduce methods for volume investigation, ion flux analysis and molecular modeling. The visualization methods are based on a multidimensional data model to accommodate complex datasets. The software uses vector processing and multiple processors to accelerate volume rendering and achieve interactive rendering. The algorithms are based on human visual perception and allow the observer a wide range of mixed render modes. The software was used to reconstruct the pituitary development in zebrafish and observe the degeneration of neurons after injury in a mouse model. Calicum indicator dyes have long been used to study calcium fluxes. We optimized the imaging method to minimize impact on the cell. Live cells were imaged continuously for 45 minutes and subjected to increasing does of a drug. We correlated the amplitude of calcium oscillations to increasing doses of a drug and obtain single cell dose response curves. Because this method is very sensitive and measures single cell responses it has potential in drug discovery and characterization. Microtubules form a dynamic cytoskeleton, which is responsible for cell shape, intracellular transport and has an integral role in mitosis. A hallmark of microtubule organization is lateral interactions. Microtubules are bundles by proteins into dense structures. To estimate the contribution of this bundling process, we created a fractal model of microtubule organization. This model demonstrates that morphology of complex microtubule arrays can be explained by bundling alone. In summary we showed that advances in software for visualization, data analysis and modeling lead to new discoveries.
Background: The frequency of the most observed cancer, Non Hodgkin Lymphoma (NHL), is further rising. Diffuse large B-cell lymphoma (DLBCL) is the most common of the NHLs. There are two subgroups of DLBCL with different gene expression patterns: ABC (“Activated B-like DLBCL”) and GCB (“Germinal Center B-like DLBCL”). Without therapy the patients often die within a few months, the ABC type exhibits the more aggressive behaviour. A further B-cell lymphoma is the Mantle cell lymphoma (MCL). It is rare and shows very poor prognosis. There is no cure yet. Methods: In this project these B-cell lymphomas were examined with methods from bioinformatics, to find new characteristics or undiscovered events on the molecular level. This would improve understanding and therapy of lymphomas. For this purpose we used survival, gene expression and comparative genomic hybridization (CGH) data. In some clinical studies, you get large data sets, from which one can reveal yet unknown trends. Results (MCL): The published proliferation signature correlates directly with survival. Exploratory analyses of gene expression and CGH data of MCL samples (n=71) revealed a valid grouping according to the median of the proliferation signature values. The second axis of correspondence analysis distinguishes between good and bad prognosis. Statistical testing (moderate t-test, Wilcoxon rank-sum test) showed differences in the cell cycle and delivered a network of kinases, which are responsible for the difference between good and bad prognosis. A set of seven genes (CENPE, CDC20, HPRT1, CDC2, BIRC5, ASPM, IGF2BP3) predicted, similarly well, survival patterns as proliferation signature with 20 genes. Furthermore, some bands could be associated with prognosis in the explorative analysis (chromosome 9: 9p24, 9p23, 9p22, 9p21, 9q33 and 9q34). Results (DLBCL): New normalization of gene expression data of DLBCL patients revealed better separation of risk groups by the 2002 published signature based predictor. We could achieve, similarly well, a separation with six genes. Exploratory analysis of gene expression data could confirm the subgroups ABC and GCB. We recognized a clear difference in early and late cell cycle stages of cell cycle genes, which can separate ABC and GCB. Classical lymphoma and best separating genes form a network, which can classify and explain the ABC and GCB groups. Together with gene sets which identify ABC and GCB we get a network, which can classify and explain the ABC and GCB groups (ASB13, BCL2, BCL6, BCL7A, CCND2, COL3A1, CTGF, FN1, FOXP1, IGHM, IRF4, LMO2, LRMP, MAPK10, MME, MYBL1, NEIL1 and SH3BP5; Altogether these findings are useful for diagnosis, prognosis and therapy (cytostatic drugs).
Neural crest cells and sensory neurons are two prominent cell populations which are induced at the border between neural and non-neural ectoderm during early vertebrate development. The neural crest cells are multipotent and highly migratory precursors that give rise to face cartilage, peripheral neurons, glia cells, pigment cells and many other cell types unique to vertebrates. Sensory neurons are located dorsally in the neural tube and are essential for sensing and converting environmental stimuli into electrical motor reflexes. In my PhD thesis, I obtained novel insights into the complex processes of cell induction at the neural plate border by investigating the regulation and function of mdkb in zebrafish. First, it was possible to demonstrate that mdkb expression is spatiotemporally correlated with the induction of neural crest cells and primary sensory neurons at the neural plate border. Second, it became evident that the expression of mdkb is activated by known neural crest cell inducing signals, like Wnts, FGFs and RA, but that it is independent of Delta-Notch signals essential for lateral inhibition. Knockdown experiments showed that mdkb function is necessary for induction of neural crest cells and sensory neurons at the neural plate border, probably through determination of a common pool of progenitor cells during gastrulation. The present study also used the advantages of the zebrafish model system to investigate the in vivo function of all midkine gene family members during early brain development. In contrast to the situation in mouse, all three zebrafish genes show distinct expression patterns throughout CNS development. mdka, mdkb and ptn expression is detected in mostly non-overlapping patterns during embryonic brain development in the telencephalon, the mid-hindbrain boundary and the rhombencephalon. The possibility of simultaneously knocking down two or even three mRNAs by injection of morpholino mixtures allowed the investigation of functional redundancy of midkine factors during brain formation. Knockdown of Midkine proteins revealed characteristic defects in brain patterning indicating their association with the establishment of prominent signaling centers such as the mid-hindbrain boundary and rhombomere 4. Interestingly, combined knockdown of mdka, mdkb and ptn or single knockdown of ptn alone prevented correct formation of somites, either by interfering with the shifting of the somite maturation front or interferance with cell adhesion in the PSM. Thus, Ptn was identified as a novel secreted regulator of segmentation in zebrafish.
Interleukin-5 (IL-5) is a member of the hematopoietic class I cytokines and is specifically involved in eosinophil activation. IL-5 plays an important role in disease conditions such as allergic asthma and other hypereosinophilias, which are characterized by highly increased levels of eosinophils in peripheral blood and tissues. The IL-5 receptor is a heterodimer consisting of a binding alpha subunit (IL- 5Rα) and a common beta subunit (IL-5Rβ). This IL-5Rβ is shared with the IL-3 and GM-CSF receptors. The IL-5Rα is required for ligand-specific binding, whereas the association of the IL-5Rβ subunit triggers intracellular signal transduction. Previous studies have described the crystallographic structure of human IL-5 (hIL-5), as well as that of the common IL-5Rβ chain (IL-5Rβc) However, no experimental structural data are yet available for the interaction of the high-affinity IL-5 receptor IL-5Rα with its ligand IL-5. Therefore, this thesis had the principle objective to gain new insights into the basis of this important agonist-receptor interaction. In particular, data on the recombinant expression, purification and preparation of the binary complex of hIL-5 bound to the receptor ectodomain of hIL-5Rα are shown, as well as the subsequent crystal structure analysis of the binary ligand-receptor (hIL-5Rα/hIL-5) complex. Both proteins were expressed in an Escherichia coli expression system, purified to homogeneity, and crystallized. However, since the initial analysis of these crystals did not show any X-ray diffraction, each step of the preparation and crystallization procedure had to be stepwise optimized. Several improvements proved to be crucial for obtaining crystals suitable for structure analysis. A free cysteine residue in the N-terminal domain of the hIL-5Rα ectodomain protein was mutated to alanine to remove protein heterogeneity. In addition, hIL-5 affinity chromatography of the receptor protein proved to be absolutely crucial for crystal quality. Additive screening using the initial crystallization condition finally yielded crystals of the binary complex, which diffracted to 2.5Å resolution and were suitable for structure analysis. The preliminary structure data demonstrate a new receptor architecture for the IL-5Rα ligand-binding domain, which has no similarities to other cytokine class I receptor structures known so far. The complex structure demonstrates that the ligand-binding region of human IL-5Rα is dispersed over all three extracellular domains, and adopts a binding topology in which the cytokine recognition motif (CRM) needs the first Fn-III domain of the human IL-5Rα to bind the ligand. In a second project, a prokaryotic expression system for murine IL-5 (mIL-5) was established to allow the production of mIL-5 and mIL-5 antagonist that should facilitate functional studies in mice. Since the expression of mIL-5 in E. coli had never been successful so far, a fusion protein system was generated expressing high yields of mIL-5. Chemical cleavage with cyanogen bromide (CNBr) was used to release mIL-5 monomers, which were subsequently purified and refolded. This technique yielded an active murine IL-5 dimer as confirmed by TF-1 cell proliferation assays. The protein was crystallized and the structure of mIL-5 could be determined at 2.5Å resolution. The molecular structure revealed a symmetrical left-handed four helices bundle dimer similar to human IL-5. Analysis of the structure-/function relationship allowed us to design specific mIL-5 antagonist molecules, which are still under examination. Taken together, these findings provide further insights in the IL-5 and IL-5R interaction which may help to further understand and depict this and other cytokine-receptor interactions of similar architecture, e.g. the IL-13 ligand-receptor system. Ultimately, this may represent another piece of puzzle in the attempts to rationally design and engineer novel IL-5-related pharmacological therapeutics.
1. Host plant finding in walking herbivorous beetles is still poorly understood. Analysis of small-scale movement patterns under semi-natural conditions can be a useful tool to detect behavioural responses towards host plant cues. 2. In this study, the small-scale movement behaviour of the monophagous leaf beetle Cassida canaliculata Laich. (Coleoptera: Chrysomelidae) was studied in a semi-natural arena (r = 1 m). In three different settings, a host (Salvia pratensis L., Lamiales: Lamiaceae), a non-host (Rumex conglomeratus Murr., Caryophyllales: Polygonaceae), or no plant was presented in the centre of the arena. 3. The beetles showed no differences in the absolute movement variables, straightness and mean walking speed, between the three settings. However, the relative movement variables, mean distance to the centre and mean angular deviation from walking straight to the centre, were significantly smaller when a host plant was offered. Likewise, the angular deviation from walking straight to the centre tended to decline with decreasing distance from the centre. Finally, significantly more beetles were found on the host than on the non-host at the end of all the trials. 4. It is concluded that C. canaliculata is able to recognise its host plant from a distance. Whether olfactory or visual cues (or a combination of both) are used to find the host plant remains to be elucidated by further studies.
B cells play diverse roles in the immunopathogensis of autoimmune diseases several approaches targeting B cell directly or indirectly are in clinical practice in the treatment of autoimmunity. In this regard, temporal B cell depletion by rituximab (anti CD20 antibody) is being appreciated and gaining more importance in recent years. To date, little is known about the regeneration profile of B cells following B cell depletion. We wanted to investigate the early replenishing B cells and examine the dynamic changes in the repertoire. we studied the immunoglobulin receptor (IgR) modulation of Ig-VH4 genes as representative of the heavy chain family. Five patients were included in the study and therapy induced alterations were assessed. Three time points namely before therapy, early regeneration phase (ERP- the early time point during regeneration where just above 1% B cells were found in the peripheral lymphocyte pool) and later regeneration phase (LRP- which commenced 2-3 months following ERP) were chosen. In three patients (A-C), Ig-VH4 genes were amplified from total genomic DNA during the above-mentioned all time points and in another two patients (D and E), Ig genes during ERP were studied by single cell amplification technique. Firstly, B cell regeneration followed the characteristic regeneration pattern as reported by several groups, with a predominant circulation of CD38hi expressing plasma cells and immature B cells in the ERP. During LRP, the proportion of these cells reduced relatively and the levels of naïve B cells rose gradually. On a molecular level, Ig-VH4 variable gene usage prior and post B cell depletion was determined and it was noticed that a diverse set of Ig-VH4 genes were employed in the repertoire before and after therapy. Mini gene segments such as VH4-34 and VH-4-39, which were reported to be connected with autoimmunity, were over expressed in the B cell repertoire before therapy. Profound changes were noticed in the early reemerging repertoire with a relatively increased population of intensely mutated B cells. These B cells acquired >=9 mutations in the Ig genes. Immunophenotyping with specific surface markers revealed that these highly mutated B cells evolve from the isotype-switched memory compartment especially the plasma cells. To support the hypothesis that the highly mutated B cells observed during ERP were plasma cells we carried out single cell amplification of individual plasma cells in another two patients during ERP and compared the mutational load, which remained similar. Actually plasma cells do not express CD20 on their surface and are not eliminated by rituximab therapy. However they were not observed in the peripheral blood following B cell depletion. The earliest time point when plasma cells are found again in peripheral circulation is the early recovery period (ERP). Therefore, it was intriguing to ascertain if the plasma cells were also modulated by rituximab therapy although they were not directly targeted by the therapy. We investigated if there is a therapy mediated mutational modulation of the plasma cells though these are not directly targeted by the therapy. We examined the confinement of mutations to the pre-defined RGYW/WRCY hotspot motifs (R=purine, Y=pyrimidine, W=A/T) in the plasma cells, which provides information on the involvement of T cells in B cell somatic hypermutation (SHM). Plasma cells before rituximab manifested the characteristics of active disease, which was revealed by restricted mutational targeting to the RGYW/WRCY motifs. The reemerging plasma cells during ERP had an increased targeting of the RGYW/WRCY motifs which indicated for a more pronounced T cell mediated B cell mutations which is the scenario observed in the healthy subjects. To further support the hypothesis of rituximab-mediated plasma cell modulation, we delineated the replacement to silent mutations ratio (R/S) in the hypervariable regions (CDRs) of the plasma cell Ig sequences. Within our study, the mean R/S ratio in the plasma cell CDRs of the patient group was relatively low (1.87) before rituximab treatment and interestingly this ratio increased significantly in the recirculating plasma cells to values of 2.67 and 3.60 in ERP and LRP status respectively. The increase in R/S ratios in reemerging plasma cells can be interpreted as a shaping of the Ig-repertoire by positive antigen selection as seen in healthy individuals. To conclude, our study demonstrates temporal B cell depletion by rituximab therapy seems to modulate also the plasma cell compartment, which is not directly targeted by the therapy. Modulation of plasma cells in RA could be also used as a potential biomarker in studying the effective response in RA treatment. This needs to be further explored to gain deeper insights into the underlying processes, which may be influenced by future therapies.
The process of sex-determination can be better understood through examinations of developing organs and cells, which are involved in the formation of undifferentiated gonad. This mechanisms show in fish a broad variety, ranging from hermaphroditism to gonochorism and environmental to genetic sex determination. Hormones and abiotic factors such as temperature and pH can influence teleost development and reproductive traits. These factors are vulnerable to pollutants and climate changes. Therefore, it is important to examine gonad development and sex-determination/differentiation in teleost fish. Teleost fish are the largest known group of vertebrates with approximately 25,000 species and are used for such kind of examinations as model organisms. Recently, in Oryzias latipes (medaka), dmrt1bY (or dmy), a member of the Dmrt gene family, has been described as testis-determining gene. However, this gene is not the universal master sex-determining gene in teleost fish. Although dmrt1bY is present in the most closely related species of the genus, namely Oryzias curvinotous, it is absent from other Oryzias species, like Oryzias celebensis, and other fish. During my thesis, I studied gonad development in medaka and in the closely related species Oryzias celebensis. Germ cell specification in medaka seems to be dependent on maternally provided cytoplasmatic determinants, so called germ plasm. Nanos and vasa are such germ cell specific genes. In zebrafish they are asymmetrically localized in the early embryo. I have shown that nanos mRNA is evenly distributed in the early embryo of medaka. A similar pattern has been already described for the medaka vasa homolog, olvas. This suggests differences in PGC specification in zebrafish and medaka. Further, the vasa homolog was isolated and the expression pattern examined in O. celebensis. The results show that it can be used as a germ cell specific marker. Additionally, the primordial germ cell migration in O. celebensis was followed, which is similar to medaka PGC migration. Primordial germ cell migration in vertebrates is dependent on the chemokine stromal cell-derived factor 1 (Sdf-1). Medaka has two different sdf-1 genes, sdf-1a and sdf-1b. Both genes are expressed in the lateral plate mesoderm (LPM). During late embryonic development, I could show that sdf-1a is expressed in newly formed somites and not longer in the LPM. Sdf-1b expression persisted in the posterior part of the lateral plate mesoderm in the developing gonad. In terms of early and late functions, this suggests subfunctionalization of sdf-1a and sdf-1b. In “higher” vertebrates, genes that are involved in the process of gonad development have been studied in detail, e.g. Wt1, Sox9, and Amh. I have analyzed the expression pattern of wt1 and sox9 co-orthologs and amh. In both, the medaka and O. celebensis, wt1a transcripts were localized in the LPM and its expression was similar to sdf-1a gene expression in medaka. Wt1b expression was restricted to the developing pronephric region. During later embryonic development, wt1a is specifically expressed in the somatic cells of the gonad primordium in both sexes. This is the first time that in fish wt1 gene expression in developing gonads has been described. Therefore, this result suggests that wt1a is involved in the formation of the bipotential gonad. Furthermore, I have analyzed the gonad specific function of the wt1 co-orthologs in medaka. I could show that a conditional co-regulation mechanism between Wt1a and Wt1b ensures PGC maintenance and/or survival. The expression of sox9 genes in medaka and sox9b in O. celebensis were detected in the somatic cells of the gonad primordium of both sexes. Additionally, I have shown that amh and amhrII in medaka are expressed in somatic cells of the gonad primordium of both sexes. This suggests that sox9b, amh and amhrII are involved in gonad development and have specific functions in the adult gonad. In O. celebensis I could detect an expression of dmrt1 already six days after fertilization in half of the embryos, which is similar to the dmrt1bY expression in medaka. Whether the expression of dmrt1 is male specific in O. celebensis is currently under investigation. Altogether, the obtained results provide new insights into gene expression patterns during the processes of gonad development. Furthermore, no differences in the expression pattern of wt1a and sox9b during gonad development between the medaka and O. celebensis could be detected. This might indicate that the genetic mechanisms during gonad development are similar in both species.
Aggression is a strikingly multi-faceted phenomenon occurring in vertebrates as well as in invertebrates. Despite its omnipresence, the neuronal basis of aggressive behaviours is yet barely understood. Many studies however, imply a role for biogenic amines in aggression. This PhD project aimed at contributing to the understanding of the neuronal correlates of aggression, with a main focus on the biogenic amine octopamine, using Drosophila melanogaster as the model system. In Drosophila, agonistic encounters of males and females are composed of a variety of both offensive and defensive components, some of which are displayed more often in one sex than in the other. To simplify analysis and to standardize evaluation, I chose to focus on a single indicator of aggression: the lunge, a striking feature unique to Drosophila male aggression. By evaluating the lunge I developed in cooperation with Andreas Eckart for the first time an automated, video-based analysis of Drosophila male aggression. The present software program gives the number of lunges for each fly in a certain time interval. In addition, it provides information such as the distance the fly walked and his size among others. In combination with a second software program that we developed, aggressive interactions between two male Drosophila melanogaster of a genotype of choice can now be registered either completely automatically or if preferred semi-automatically. Using these softwares, I demonstrate that (1) body size differences of 8% and higher influence the outcome of a fight in favour of the larger male; (2) walking activity alters lunge frequency with more lunges performed by more active pairs of males; (3) flies mutant for the white gene, one member of the ABC transporter family in Drosophila, are profoundly impaired in aggression, an effect that is partially due to reduced visual performance. (4) Either knocking-down white in various brain regions or chemically ablating the mushroom body located in the central brain by deleting its neuroblast precursors diminishes aggression, indicating that integrity of various neural circuits/brain regions is required for wild-type aggression to occur. Furthermore, I show that (5) flies lacking octopamine signalling but having altered tyramine signalling display hardly any lunge. A quantitative high-speed analysis revealed that lunge execution is almost indistinguishable from wild-type males. The results from the experiments in which octopamine levels and/or tyramine levels were restored suggest that an elaborate pattern of octopamine levels in time and space is required to enable flies to express wild-type aggressive behaviour.