Voloshanenko, O.; Schwartz, U.; Kranz, D.; Rauscher, B.; Linnebacher, M.; Augustin, I.; Boutros, M. (2018)
Voloshanenko, O.; Schwartz, U.; Kranz, D.; Rauscher, B.; Linnebacher, M.; Augustin, I....
Scientific Reports 8, 3178.
Leibing, T.; Géraud, C.; Augustin, I.; Boutros, M.; Augustin, H.; Okun, J.; Langhans, C.; Zierow, J.; Wohlfeil, S.; Olsavszky, V.; Schledzewski, K.; Goerdt, S.; Koch, P. (2017)
Leibing, T.; Géraud, C.; Augustin, I.; Boutros, M.; Augustin, H.; Okun, J....
Hepatology 68 (2), S. 707-722.
Augustin, I.; Dewi, D.; Hundshammer, J.; Erdmann, G.; Kerr, G.; Boutros, M. (2017)
Science Signaling 10 (461).
Wnt signaling plays an important role in the self-renewal and differentiation of stem cells. The secretion of Wnt ligands requires Evi (also known as Wls). Genetically ablating Evi provides an experimental approach to studying the consequence of depleting all redundant Wnt proteins, and overexpressing Evi enables a nonspecific means of increasing Wnt signaling. We generated Evi-deficient and Evi-overexpressing mouse embryonic stem cells (ESCs) to analyze the role of autocrine Wnt production in self-renewal and differentiation. Self-renewal was reduced in Evi-deficient ESCs and increased in Evi-overexpressing ESCs in the absence of leukemia inhibitory factor, which supports the self-renewal of ESCs. The differentiation of ESCs into cardiomyocytes was enhanced when Evi was overexpressed and teratoma formation and growth of Evi-deficient ESCs in vivo were impaired, indicating that autocrine Wnt ligands were necessary for ESC differentiation and survival. ESCs lacking autocrine Wnt signaling had mitotic defects and showed genomic instability. Together, our study demonstrates that autocrine Wnt secretion is important for the survival, chromosomal stability, differentiation, and tumorigenic potential of ESCs.
Augustin, I.; Dewi, D.; Hundshammer, J.; Rempel, E.; Brunk, F.; Boutros, M. (2016)
Stem Cell Research 17 (3), S. 607-615.
Wnt signaling plays a central role in tumor initiation and tumor progression. Mutations in Wnt pathway components, such as the tumor suppressor APC, lead to malignant transformation. While previous studies focused on Wnt-related changes in cancer cells, the impact of aberrant Wnt signaling on the tumor microenvironment is only beginning to emerge. In order to investigate the role of increased Wnt secretion on tumor growth and the microenvironment, we generated a novel germ cell tumor model by overexpressing the Wnt secretion factor Evi/Wls in mouse embryonic stem cells. Evi-overexpressing teratoma were characterized by enhanced tumor growth in supporting a tumor-promoting role of Wnt secretion. Interestingly, enhanced Evi expression correlated with impaired immune cell recruitment. Specifically, T- and B-cell infiltration was reduced in Evi-overexpressing teratomas, which was independent of teratoma size and differentiation. Our study suggests that Wnt secretion impairs immunosurveillance. Since immune cell infiltration has been shown to have prognostic value, the levels of secreted Wnt activity might impact the efficiency of cancer immunotherapy.
Scholz, B.; Korn, C.; Wojtarowicz, J.; Mogler, C.; Augustin, I.; Boutros, M.; Niehrs, C.; Augustin, H. (2016)
Scholz, B.; Korn, C.; Wojtarowicz, J.; Mogler, C.; Augustin, I.; Boutros, M....
Developmental Cell 36 (1), S. 79-93.
Brunk, F.; Augustin, I.; Meister, M.; Boutros, M.; Kyewski, B. (2015)
The Journal of Immunology 195 (11), S. 5261-5271.
Augustin, I. (2015)
Journal der Deutschen Dermatologischen Gesellschaft 13 (4), S. 302-306.
The mammalian skin mediates the primary interphase between the body and the external environment and provides the first line of defense against pathogens, mechanical trauma, sunlight injuries, and chemical stress. Proper physical, biochemical, and immunological composition of the skin is necessary to maintain its barrier function. Therefore, the skin reflects a complex dynamic organ with high cellular turnover during normal tissue replacement and wound repair. Stem cell reservoirs ensure constant skin renewal. Wnt signaling controls stem cell maintenance and fate decisions in various tissues and also reflects a key pathway in controlling skin development and homeostasis. Disruption of Wnt signaling in the skin causes disorders such as alopecia, chronic inflammatory skin diseases or cancer. This review summarizes the role of Wnt signaling during skin development, homeostasis, and disease.
Korn, C.; Scholz, B.; Hu, J.; Srivastava, K.; Wojtarowicz, J.; Arnsperger, T.; Adams, R.; Boutros, M.; Augustin, H.; Augustin, I. (2014)
Korn, C.; Scholz, B.; Hu, J.; Srivastava, K.; Wojtarowicz, J.; Arnsperger, T....
Development 141 (8), S. 1757-1766.
Voloshanenko, O.; Erdmann, G.; Dubash, T.; Augustin, I.; Metzig, M.; Moffa, G.; Hundsrucker, C.; Kerr, G.; Sandmann, T.; Anchang, B.; Demir, K.; Boehm, C.; Leible, S.; Ball, C.; Glimm, H.; Spang, R.; Boutros, M. (2013)
Voloshanenko, O.; Erdmann, G.; Dubash, T.; Augustin, I.; Metzig, M.; Moffa, G....
Nature Communications 4, 2610, S. 1-13.
Augustin, I.; Gross, J.; Baumann, D.; Korn, C.; Kerr, G.; Grigoryan, T.; Mauch, C.; Birchmeier, W.; Boutros, M. (2013)
Augustin, I.; Gross, J.; Baumann, D.; Korn, C.; Kerr, G.; Grigoryan, T.; Mauch, C....
Journal of Experimental Medicine 210 (9), S. 1761-1777.
Cells of the epidermis renew constantly from germinal layer stem cells. Although epithelial cell differentiation has been studied in great detail and the role of Wnt signaling in this process is well described, the contribution of epidermal Wnt secretion in epithelial cell homeostasis remains poorly understood. To analyze the role of Wnt proteins in this process, we created a conditional knockout allele of the Wnt cargo receptor Evi/Gpr177/Wntless and studied mice that lacked Evi expression in the epidermis. We found that K14-Cre, Evi-LOF mice lost their hair during the first hair cycle, showing a reddish skin with impaired skin barrier function. Expression profiling of mutant and wild-type skin revealed up-regulation of inflammation-associated genes. Furthermore, we found that Evi expression in psoriatic skin biopsies is down-regulated, suggesting that Evi-deficient mice developed skin lesions that resemble human psoriasis. Immune cell infiltration was detected in Evi-LOF skin. Interestingly, an age-dependent depletion of dendritic epidermal T cells (DETCs) and an infiltration of γδlow T cells in Evi mutant epidermis was observed. Collectively, the described inflammatory skin phenotype in Evi-deficient mice revealed an essential role of Wnt secretion in maintaining normal skin homeostasis by enabling a balanced epidermal-dermal cross talk, which affects immune cell recruitment and DETC survival.
Augustin, I.; Goidts, V.; Bongers, A.; Kerr, G.; Vollert, G.; Radlwimmer, B.; Hartmann, C.; Herold-Mende, C.; Reifenberger, G.; von Deimling, A.; Boutros, M. (2012)
Augustin, I.; Goidts, V.; Bongers, A.; Kerr, G.; Vollert, G.; Radlwimmer, B....
EMBO Molecular Medicine 4 (1), S. 38-51.
Malignant astrocytomas are highly aggressive brain tumours with poor prognosis. While a number of structural genomic changes and dysregulation of signalling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Here, we show that the Wnt‐specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas. Evi/Wls is a core Wnt signalling component and a specific regulator of pan‐Wnt protein secretion, affecting both canonical and non‐canonical signalling. We demonstrate that its depletion in glioma and glioma‐derived stem‐like cells led to decreased cell proliferation and apoptosis. Furthermore, Evi/Wls silencing in glioma cells reduced cell migration and the capacity to form tumours in vivo. We further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signalling. Taken together, our study identifies Evi/Wls as an essential regulator of glioma tumourigenesis, identifying a pathway‐specific protein trafficking factor as an oncogene and offering novel therapeutic options to interfere with the aberrant regulation of growth factors at the site of production.
Rosenmund, C.; Sigler, A.; Augustin, I.; Reim, K.; Brose, N.; Rhee, J. (2002)
Neuron 33 (3), S. 411-424.
Rhee, J.; Betz, A.; Pyott, S.; Reim, K.; Varoqueaux, F.; Augustin, I.; Hesse, D.; Südhof, T.; Takahashi, M.; Rosenmund, C.; Brose, N. (2002)
Rhee, J.; Betz, A.; Pyott, S.; Reim, K.; Varoqueaux, F.; Augustin, I.; Hesse, D....
Cell 108 (1), S. 121-133.
Schmitz, F.; Augustin, I.; Brose, N. (2001)
Brain Research 895 (1-2), S. 258-263.
Augustin, I.; Korte, S.; Rickmann, M.; Kretzschmar, H.; Südhof, T.; Herms, J.; Brose, N. (2001)
Augustin, I.; Korte, S.; Rickmann, M.; Kretzschmar, H.; Südhof, T.; Herms, J....
The Journal of Neuroscience 21 (1), S. 10-17.
Munc13 proteins form a family of three, primarily brain-specific phorbol ester receptors (Munc13-1/2/3) in mammals. Munc13-1 is a component of presynaptic active zones in which it acts as an essential synaptic vesicle priming protein. In contrast to Munc13-1, which is present in most neurons throughout the rat and mouse CNS, Munc13-3 is almost exclusively expressed in the cerebellum. Munc13-3 mRNA is present in granule and Purkinje cells but absent from glia cells. Munc13-3 protein is localized to the synaptic neuropil of the cerebellar molecular layer but is not found in Purkinje cell dendrites, suggesting that Munc13-3, like Munc13-1, is a presynaptic protein at parallel fiber–Purkinje cell synapses. To examine the role of Munc13-3 in cerebellar physiology, we generated Munc13-3-deficient mutant mice. Munc13-3 deletion mutants exhibit increased paired-pulse facilitation at parallel fiber–Purkinje cell synapses. In addition, mutant mice display normal spontaneous motor activity but have an impaired ability to learn complex motor tasks. Our data demonstrate that Munc13-3 regulates synaptic transmission at parallel fiber–Purkinje cell synapses. We propose that Munc13-3 acts at a similar step of the synaptic vesicle cycle as does Munc13-1, albeit with less efficiency. In view of the present data and the well established vesicle priming function of Munc13-1, it is likely that Munc13-3-loss leads to a reduction in release probability at parallel fiber–Purkinje cell synapses by interfering with vesicle priming. This, in turn, would lead to increases in paired-pulse facilitation and could contribute to the observed deficit in motor learning.
Augustin, I.; Rosenmund, C.; Südhof, T.; Brose, N. (1999)
Nature 400, S. 457-461.
Neurotransmitter release at synapses between nerve cells is mediated by calcium-triggered exocytotic fusion of synaptic vesicles1. Before fusion, vesicles dock at the presynaptic release site where they mature to a fusion-competent state1,2. Here we identify Munc13-1, a brain-specific presynaptic phorbol ester receptor3,4, as an essential protein for synaptic vesicle maturation. We show that glutamatergic hippocampal neurons from mice lacking Munc13-1 form ultrastructurally normal synapses whose synaptic-vesicle cycle is arrested at the maturation step. Transmitter release from mutant synapses cannot be triggered by action potentials, calcium-ionophores or hypertonic sucrose solution. In contrast, release evoked by α-latrotoxin is indistinguishable from wild-type controls, indicating that the toxin can bypass Munc13-1-mediated vesicle maturation. A small subpopulation of synapses of any given glutamatergic neuron as well as all synapses of GABA (γ-aminobutyric acid)-containing neurons are unaffected by Munc13-1 loss, demonstrating the existence of multiple and transmitter-specific synaptic vesicle maturation processes in synapses.
Augustin, I.; Betz, A.; Herrmann, C.; Jo, T.; Brose, N. (1999)
Biochemical Journal (337), S. 363-371.
Munc13-1, a mammalian homologue of Caenorhabditis elegans unc-13p, is a presynaptic phorbol ester receptor that enhances neurotransmitter release. In the present study we analysed the regional, cellular and subcellular expression patterns in rat of two novel Munc13 proteins, Munc13-2 and Munc13-3. We demonstrate by hybridization in situ that Munc13-1 mRNA is expressed throughout the brain, whereas Munc13-2 mRNA is preferentially present in rostral brain regions, and Munc13-3 mRNA in caudal areas. In an analysis of subcellular brain fractions with isoform-specific antibodies, we show that the novel Munc13 proteins are enriched in synapses. Immunocytochemical examination of rat cerebellar sections indicates that Munc13-3, like Munc13-1, is concentrated in presynaptic terminals. Our results characterize Munc13 proteins as a family of neuron-specific, synaptic molecules that bind to syntaxin, an essential mediator of neurotransmitter release. Munc13-2 and Munc13-3 are expressed in a complementary fashion and might act in concert with Munc13-1 to modulate neurotransmitter release.
Betz, A.; Ashery, U.; Rickmann, M.; Augustin, I.; Neher, E.; Südhof, T.; Rettig, J.; Brose, N. (1998)
Betz, A.; Ashery, U.; Rickmann, M.; Augustin, I.; Neher, E.; Südhof, T.; Rettig, J....
Neuron 21 (1), S. 123-136.