Biology subjects

Schäfer, T.

Publications and source records attributed to Schäfer, T..

4 recordsLinked to original sources

bioRxiv2026

Oxytocin receptor Gαi signaling drives valence reassignment to facilitate reversal of social trauma-induced avoidance

Traumatic social experiences often generate social deficits that form the core symptom of psychopathologies like social anxiety disorder (SAD). The failure to overwrite these aversive social associations is a fundamental barrier to recovery from SAD. Using the mouse social fear conditioning (SFC) paradigm, we identify a discrete population of oxytocin receptor (OXTR)-expressing neurons in the caudal lateral septum (LScOXTR) that act as a critical hub for adaptive learning during social fear extinction. Using calcium imaging in mice undergoing extinction training, we show that successful valence reassignment is best predicted by the precise temporal inhibition of LScOXTR neurons during the contact phase of social investigation. This contact-associated suppression of LScOXTR neurons was absent in mice that failed to extinguish fear. Notably, successful extinction was also associated with enhanced oxitocinerg innervation within the LSc. Chemogenetic silencing of LScOXTR neurons prior to extinction impaired extinction, indicating that a specific temporal activity pattern of LScOXTR neurons is necessary for adaptive learning. Pharmacological dissection of downstream OXTR signaling revealed that selective activation of Gi-coupled, but not Gq-coupled, signaling accelerated extinction and promoted social approach. Our findings establish that extinction success is governed by the temporally precise, Gi-mediated silencing of LScOXTR neurons during social contact, revealing a novel mechanism for adaptive social valence processing with direct implications for treatment-resistant SAD.

neuroscience↗

bioRxiv2024

Changes in growth, lanthanide binding, and gene expression in Pseudomonas alloputida KT2440 in response to light and heavy lanthanides

Pseudomonas alloputida KT2440 is a ubiquitous, soil-dwelling bacterium that metabolizes recalcitrant and volatile carbon sources. The latter are utilized by two redundant, Ca- and lanthanide (Ln)-dependent, pyrroloquinoline quinone-dependent alcohol dehydrogenases (PQQ ADH), PedE and PedH, whose expression is regulated by Ln availability. P. alloputida KT2440 is the best-studied, non-methylotroph in the context of Ln-utilization. We report the most comprehensive differential gene expression analysis, to date, for any Ln-utilizing microbe. Combined with microfluidic cultivation and single-cell elemental analysis, we studied the impact of light and heavy Ln when growing P. alloputida KT2440 with 2-phenylethanol as the carbon and energy source. Light Ln (La, Ce, Nd) and a mixture of light and heavy Ln (La, Ce, Nd, Dy, Ho, Er, Yb) had a positive effect on growth, while supplementation with heavy Ln (Dy, Ho, Er, Yb) exerted fitness costs. These were likely a consequence of mismetallation and oxidative stress. Gene expression analysis showed that the Ln sensing and signaling machinery, the two-component system PedS2R2 and PedH, responds differently to (non-)utilizable Ln. We broadened the understanding of the Ln switch in P. alloputida KT2440 and could show that it operates as a dimmer switch, modulating the pool of PQQ ADH dependent on Ln availability. Determined quantities of cell-associated Ln suggest a role for Ln beyond alcohol oxidation. The usability of Ln governs the response of P. alloputida KT2440 to different Ln elements. ImportanceThe Ln switch, the inverse regulation of Ca- and Ln-dependent PQQ ADH dependent on Ln availability in organisms featuring both, is central to our understanding of Ln utilization. Although the preference of bacteria for light Ln is well known, the effect of different Ln, light and heavy, on growth and gene expression has rarely been studied. We provide evidence for a dimmer switch-like regulation of Ca- and Ln-dependent PQQ ADH in P. alloputida KT2440, and could show that the response to (non-)utilizable Ln differs depending on the element. Ln commonly co-occur in nature. Our findings underline that Ln-utilizing microbes must be able to discriminate between Ln to use them effectively. Considering the prevalence of Ln-dependent proteins in many microbial taxa, more work addressing Ln sensing and signaling is needed. Ln availability likely necessitates different adaptations regarding Ln utilization.

microbiology↗

bioRxiv2023

Crosslinking by ZapD drives the assembly of short, discontinuous FtsZ filaments into ring-like structures in solution

Bacterial cell division relies on the Z ring, a cytoskeletal structure that acts as a scaffold for the assembly of the divisome. To date, the detailed mechanisms underlying the assembly and stabilization of the Z ring remain elusive. This study highlights the role of the FtsZ-associated protein (Zap) ZapD in the assembly and stabilization of Z-ring-like structures via filament crosslinking. Using cryo-electron tomography and biochemical analysis, we show that, at equimolar concentrations of ZapD and FtsZ, ZapD induces the formation of toroidal structures composed of short, curved FtsZ filaments that are crosslinked vertically, but also laterally and diagonally. At higher concentrations of ZapD, regularly spaced ZapD dimers crosslink FtsZ filaments from above, resulting in the formation of straight bundles. Despite the simplicity of this reconstituted system, these findings provide valuable insights into the structural organization and stabilization of the Z ring by Zap proteins in bacterial cells, revealing the key role of optimal crosslinking density and geometry in enabling filament curvature and ring formation.

biochemistry↗

bioRxiv2018

The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction

BackgroundAlveolar echinococcosis (AE) is a lethal zoonosis caused by the metacestode larva of the tapeworm Echinococcus multilocularis. The infection is characterized by tumour-like growth of the metacestode within the host liver, leading to extensive fibrosis and organ-failure. The molecular mechanisms of parasite organ tropism towards the liver and influences of liver cytokines and hormones on parasite development are little studied to date.\n\nMethodology/Principal findingsWe show that the E. multilocularis larval stage expresses three members of the fibroblast growth factor (FGF) receptor family with homology to human FGF receptors. Using the Xenopus expression system we demonstrate that all three Echinococcus FGF receptors are activated in response to human acidic and basic FGF, which are present in the liver. In all three cases, activation could be prevented by addition of the tyrosine kinase inhibitor BIBF 1120, which is used to treat human cancer. At physiological concentrations, acidic and basic FGF significantly stimulated the formation of metacestode vesicles from parasite stem cells in vitro and supported metacestode growth. Furthermore, the parasites mitogen activated protein kinase signalling system was stimulated upon addition of human FGF. The survival of metacestode vesicles and parasite stem cells were drastically affected in vitro in the presence of BIBF 1120.\n\nConclusions/SignificanceOur data indicate that mammalian FGF, which is present in the liver and upregulated during fibrosis, supports the establishment of the Echinococcus metacestode during AE by acting on an evolutionarily conserved parasite FGF signalling system. These data are valuable for understanding molecular mechanisms of organ tropism and host-parasite interaction in AE. Furthermore, our data indicate that the parasites FGF signalling systems are promising targets for the development of novel drugs against AE.\n\nAuthor summaryTo ensure proper communication between their different cell populations, animals rely on secreted hormones and cytokines that act on receptors of target cells. Most of the respective cytokines, such as FGFs, evolved over 500 million years ago and are present in similar form in all animals, including parasitic worms. The authors of this study show that the metacestode larva of the tapeworm E. multilocularis, which grows like a malignant tumor within the host liver, expresses molecules with homology to FGF receptors from mammals. The authors show that human FGF, which is abundantly present in the liver, stimulates metacestode development and that all parasite FGF receptors are activated by human FGF, despite 500 million years of evolutionary distance between both systems. This indicates that cells of the Echinococcus metacestode can directly communicate with cells of the mammalian host using evolutionarily conserved signaling molecules. This mode of host-pathogen interaction is unique for helminths and does not occur between mammals and single-celled pathogens such as protozoans or bacteria. The authors finally demonstrate that BIBF 1120, a drug used to treat human cancer, targets the Echinococcus FGF receptors and leads to parasite death. This opens new ways for the development of anti-parasitic drugs.

zoology↗