1. Molecularization of Hydra
- Klimovich A, Wittlieb J, Bosch TCG (2019) Transgenesis in Hydra to characterize gene function and visualize cell behaviour. Nature Protocol, https://rdcu.be/bFvBI pdficon
Novel computational tools and genomic resources have brought a molecular perspective on the Hydra stem cell system. A major breakthrough in research on cnidarian development came with the generation of stably transgenic Hydra by the Bosch lab using embryo injection (Wittlieb et al., 2006). This opened up a new range of experimental possibilities for studying regeneration and cellular behavior in vivo in this model organism (Siebert et al., 2008; Wittlieb et al., 2006; Khalturin et al., 2007; Gee et al., 2010; Nakamura et al., 2011; Böhm et al., 2012; Franzenburg et al., 2012) indicating the value of this approach. The successful creation of transgenic Hydra expressing GFP in all three stem cell lineages (Hemmrich et al., 2012) has greatly facilitated progress in getting insights of general relevance into stem cell biology including cellular senescence, lineage programming, the role of extrinsic signals in fate determination and tissue homeostasis, and the evolutionary origin of these cells. Loss-of-function approaches based on hairpin constructs have been successfully used to knockdown both immune (Franzenburg et al., PNAS 2012, PNAS 2013) as well as stem cell transcripts (Boehm et al., PNAS 2012).
We also provide a comparative genomics platform (http://www.compagen.org/) which provides access to a large set of genome and transcriptome sequences from basal metazoans including sponges and Cnidaria species. Since the genome organization and genome content of Cnidaria is remarkably similar to that of bilaterians, these animals offer unique insights into the content of the “genetic tool kit” present in the Cnidarian–bilaterian ancestor.
2. Stem cells, aging and the origin of cancer
The dynamic control of stem cell populations in response to external stimuli is critical to organismal adaptation to environmental conditions. This complexity is poorly understood. We have shown that stem cell maintenance in Hydra depends on transcription factor FoxO – which may account for the potential immortality of the animals (Boehm et al., 2012, 2013).
Stem cells in Hydra represent one of the most ancient stem cell systems in the animal kingdom and, therefore, provide informations for reconstructing the early history of stem cell control mechanisms. A major puzzle in developmental biology is why stem cells in most species have a limited proliferating potential while in Hydra they appear to proliferate continuously. Attempting to identify the underlying cellular and molecular mechanisms, that account for such species differences and that in particular are responsible for Hydra´s ability to continuously proliferate, is the basis of the research in the Bosch lab.
A hallmark of aging is stem cell senescence, the decline of functionality and number of somatic stem cells, resulting in an impaired regenerative capacity and reduced tissue function. In addition, aging is characterized by profound remodelling of the immune system and a quantitative decline of adequate immune responses, a phenomenon referred to as immune-senescence. Yet, what is causing stem cell and immune-senescence? The Bosch lab has shown that Hydra transcription factor FoxO modulates both stem cell proliferation and innate immunity, lending strong support to a role of FoxO as critical rate-of-aging regulator from Hydra to human. Constructing a model of how FoxO responds to diverse environmental factors provides a framework for how stem cell factors might contribute to aging.
- Finlay B, Pettersson S, Melby M, Bosch TCG (2019) The microbiome mediates environmental effects on ageing. BioEssays, e1800257. doi: 10.1002/bies.201800257
- von Frieling J, Fink C, Hamm J, Klischies K, Forster M, Bosch TCG, Roeder T, Rosenstiel P, Sommer F (2018). Grow with the challenge – microbial effects on epithelial proliferation, carcinogenesis and cancer therapy. Front Microbiol., 9:2020. doi: 10.3389/fmicb.2018.02020
- Klimovich A, Rehm A, Wittlieb J, Herbst E, Benavente R, Bosch TC, . Non-senescent Hydra tolerates severe disturbances in the nuclear lamina. Aging (Albany NY). 2018; 10:951-972.
- Mortzfeld BM, Taubenheim J, Fraune S, Klimovich AV, Bosch TCG (2018). Stem cell transcription factor FoxO controls microbiome resilience in Hydra. Front Microbiol., 9:629.
- Mortzfeld B and TCG Bosch (2017) Eco-Ageing: stem cells and microbes are controlled by ageing antagonist FoxO. Current Opinion in Microbiology, 38:181-187
- Boehm AM, G Hemmrich, K Khalturin, M Puchert, F Anton-Erxleben, J Wittlieb, UC Klostermeier, P Rosenstiel, H-H Oberg, and TCG Bosch (2012) FoxO is a critical regulator of stem cell maintenance and immortality in Hydra. Proc Natl Acad Sci USA, 109(48):19697-702
3.Tumours have deep roots in evolution
Stem cells emerged in evolution at the point of transition to stable multicellularity. This increase in hierarchical complexity requires robust mechanisms to maintain tissue homeostasis and organism integrity, and to stably interact with the environment. Dysfunction of stem cell activity is expected to lead to cancer formation. Computational analysis of genes involved in cancer formation revealed their early emergence in metazoan evolution and predicted that all metazoans might be prone to develop tumors (Domazet-Lošo & Tautz, 2010). Recently we provided the first evidence for naturally occurring bona fide cancer in two species of Hydra (Domazet-Lošo, Klimovich et al., 2014). Histological, cellular and molecular data reveal that tumor cells originate by differentiation arrest of female-restricted germ-line progenitors. The tumor cells have migration capacity, are able to induce de novo tumor formation, and show a greatly altered transcriptome that mimics expression shifts in vertebrate cancers. Our study revisits the essential role of differentiation arrest and resistance to apoptosis in driving cancerogenesis. In sum, our findings suggest that evolutionary origin of spontaneous cancers dates back to the origin of Metazoa, and imply that the ability for tumor formation goes side by side with such evolutionary innovations as multicellularity and stem cells.
- Rathje K, Mortzfeld B, Hoeppner MP, Taubenheim J, Bosch TCG, Klimovich A (2020) Dynamic interactions within the host-associated microbiota cause tumor formation in the basal metazoan Hydra. PLoS Pathog. 16(3):e1008375.
- Domazet-Lošo T, A Klimovich, B Anokhin, F Anton-Erxleben, M Hamm, C Lange, and TCG Bosch (2014) Naturally occurring tumors in the basal metazoan Hydra. Nature Communications 5 (4222) doi:10.1038/ncomms5222
4. Ecological developmental neurobiology
We are working on a better understanding of the function of the nervous system in the holobiont Hydra, which is among the first metazoans that contain neurons. We discovered that the nervous system, with its rich repertoire of neuropeptides, is involved in controlling resident beneficial microbes and that microbes affect the animal’s behavior by directly interfering with neuronal receptors. These findings provide new insight into the original role of the nervous system, and suggest that it emerged to orchestrate multiple functions including host-microbiome interactions.
- Klimovich A, Giacomello S, Björklund Å, Faure L, Kaucka M, Giez C, Murillo-Rincon AP, Matt A-S, Willoweit-Ohl D, Crupi G, de Anda J, Wong GCL, D’Amato M, Adameyko I, Bosch TCG (2020) Prototypical pacemaker neurons interact with the resident microbiota. Proc Natl Acad Sci US, July 9 2020
- Klimovich, A. V. and Bosch, T. C. (2018), Rethinking the Role of the Nervous System: Lessons From the Hydra Holobiont. BioEssays doi:10.1002/bies.201800060
- Murillo-Rincon AP, Klimovich A, Pemöller E, Taubenheim J, Mortzfeld B, Augustin R, Bosch TCG (2017) Spontaneous body contractions are modulated by the microbiome of Hydra. Sci Rep. 7(1):15937
- Bosch T.C.G., A. Klimovich, T. Domazet-Lošo, S. Gründer, T.W. Holstein, G. Jékely, D.J. Miller, A.P. Murillo-Rincon, F. Rentzsch, G.S. Richards, K. Schröder, U. Technau, R. Yuste (2017) Back to the Basics: Cnidarians Start to Fire. Trends in Neurosciences, 40(2): 92 – 105
- Augustin R, K Schröder, AP Murillo Rincón, S Fraune, F Anton-Erxleben, E-M Herbst, J Wittlieb1, M Schwentner, J Grötzinger, TM Wassenaar, TCG Bosch (2017) A secreted antibacterial neuropeptide shapes the microbiome in Hydra. Nature Comm., 8(1):69
Our current research is focused on uncovering the common rules and principles that govern the interaction between neurons and microbes and the extent to which such laws might apply to other and more complex organisms. Current projects include approaches towards understanding:
- Do microbes play a role in Hydra´s early embryonic development? And more specifically, do resident microbiota influence neurogenesis in embryos and/or in adults? Is the resident microbiota involved in educating neuronal precursor cells/stem cells which, in turn, influence the composition of the microbiota? (Project C1 in CRC 1182)
- What are the fundamental principles underlying growth and formation of the nerve net when developing Hydra embryos/hatchlings are exposed to different environmental stimuli? What are the minimal requirements for neuronal circuits for processing sensory information? Answering these questions will contribute to the understanding of the essential components of an ancestral and functional neuronal circuit and provide conceptual insights into the complexity of neural circuit growth with regard to sensory information processing (proposed project A1 in CRC 1461).
- “One of the greatest accomplishments in the evolution of development is behaviour” (John Tyler Bonner in “The evolution of complexity”, 1988). We are interested in understanding how the high degree of complexity in a large central nervous system works in any profound way. Is the general trend towards more complex and flexible behavior up the evolutionary scale from Hydra to man strictly correlated with the number of neurons?
5. Rethinking the role of immunity and the function of the nervous system
5.1. The ability of multicellular organisms to detect and respond to microorganisms is fundamental and has ancient evolutionary origins. Our work has shown that these apparently simple animals provide us with important information in understanding the evolution of epithelial-based innate immunity. The work has contributed to a paradigm shift in evolutionary immunology: components of the innate immune system with its host-specific antimicrobial peptides and a rich repertoire of pattern recognition receptors appear to have evolved in early branching metazoans because of the need to control the resident beneficial microbes rather than because of invasive pathogens. This conclusion is based on studies showing that individuals from different species differ greatly in their microbiota, that specific microbial communities are maintained over long periods of time, and that species-specific antimicrobial peptides account for different bacterial communities associated with closely related species. In sum
- The hydra immune system evolved because of the need to control resident microbiota
- Defense against invasive pathogens is secondary to the need to regulate microbiota
- Antimicrobial peptides have regulatory roles in host-microbe homeostasis and adaptations
- Developmental pathways (e.g. FoxO) interact with environmental cues such as microbes
5.2. Rethinking the Role of the Nervous System
All multicellular animals emerged in a world that was already densely populated by microbes, and all extant animals are multiorganismal and colonized by a large number of symbiotic microbes. Animal evolution, therefore, is deeply influenced by the presence of microbes. The emergence and evolution of the nervous system must be also considered in the context of host-microbe interactions. We have demonstrated that the neuron-bacteria interactions have a deep evolutionary origin, dating back to the emergence of the nervous system itself. This thinking casts a new light on the ancestral role of the nervous system, and supports the view that it was not restricted to conventional sensory-motor coordination. The first nervous systems seem to have mediated the complex interactions between the host and its microbiota, hence maintaining the holobiont. This view indicates a shared functionality between the immune system and the nervous system, pointing to a common evolutionary origin and suggesting that the nervous system evolved as much to sense and control bacteria as to coordinate movements.
- Klimovich, A. V. and Bosch, T. C. (2018), Rethinking the Role of the Nervous System: Lessons From the Hydra Holobiont. BioEssays. . doi:10.1002/bies.201800060
- Bosch TCG (2016) Emergence of immune system components in Cnidarians. In: Ratcliffe, M.J.H. (Editor in Chief), Encyclopedia of Immunobiology, Vol. 1, pp. 397–406. Oxford: Academic Press
- Bosch TCG (2014) Rethinking the role of immunity: lessons from Hydra. Trends in Immunology 35 (2014), pp. 495-502 DOI 10.1016/j.it.2014.07.008