Biology subjects

Sauter, M.

Publications and source records attributed to Sauter, M..

9 recordsLinked to original sources

bioRxiv2026

Platelet C5aR1 mediates sex-specific ischemia-driven revascularization through estradiol-dependent CXCL4 release

BackgroundSex-specific differences in cardiovascular diseases remain incompletely understood at the molecular level. ObjectivesHere, we investigated the role of the platelet complement receptor C5aR1 as a sex-specific critical mediator of revascularization following hindlimb ischemia. MethodsIschemia-driven revascularization was analyzed in the hind limb ischemia (HLI) model using wild type (WT) and complement receptor-deficient male and female mice, and involved mechanisms were analyzed in platelets and megakaryocyte-shed platelets ex vivo. ResultsIn WT mice, ischemic tissue exhibited robust complement activation with C3b and C5a accumulation that correlated strongly with deposition of the anti-angiogenic factor CXCL4 (PF4). Mechanistically, C5a stimulation of platelets triggered CXCL4 secretion, and female animals with a platelet-specific deletion of C5aR1 (using PF4-Cre-C5aR1fl/fl mice) showed a significantly delayed revascularization. Female mice exhibited substantially lower platelet C5aR1 expression, and C5a-induced CXCL4 secretion was virtually abolished compared to male animals. The sex-specific difference in tissue CXCL4 deposition was not present any more in the absence of C5aR1 from platelets. We observed that megakaryocytes, which give rise to platelets, express estradiol receptors. Importantly, estradiol stimulation of megakaryocytes suppressed C5aR1 expression during pro-platelet formation, uncovering a hormone-dependent regulatory mechanism. ConclusionsThe here described estradiol-C5aR1-CXCL4 axis provides a molecular explanation for sex-specific differences in ischemic revascularization known from patient studies. Our findings establish a novel and unexpected mechanistic link between sex hormones, a complement-platelet crosstalk and the angiogenic response to ischemia with potential clinical implications for sex-specific personalized therapeutic strategies.

immunology↗

bioRxiv2026

A multi-input optic glomerulus mediates opposing behavioral responses to visual objects

Prey, predators or conspecifics are first detected as visual objects in many seeing animals. Vision guides behavioral actions towards or away from these objects. An error in this visual perception could prove fatal. How object information is untangled to avoid errors remains unclear. Here we show that LC10d visual projection neurons in Drosophila melanogaster mediate avoidance of visual objects in the absence of a chemosensory profile. LC10d neurons are broadly tuned to objects and project to the same retinorecipient brain region that receives inputs from LC10a neurons, which are required for tracking. The descending neurons DNa10 are directly downstream of the anterior-facing LC10d sub-population and mediate LC10d-dependent avoidance. Our work demonstrates the use of two similar neuron types and chunking of the visual field into zones as strategies to disentangle similar sets of visual cues requiring nearly opposite behavioral responses.

neuroscience↗

bioRxiv2026

Platelet C5aR1 Aggravates Myocardial Infarction through Platelet-Neutrophil Interactions and CXCL4-Dependent NET Release

Platelet activation is a central driver of myocardial infarction. The complement anaphylatoxin C5a is abundantly generated during myocardial infarction, and its receptor C5aR1 is highly expressed on platelets. However, the functional role of platelet C5aR1 in myocardial infarction (MI) remains unknown. Here, we show that platelet&[ndash]expressed C5aR1 critically amplifies thromboinflammatory cardiac injury by promoting platelet&[ndash]mediated neutrophil activation after MI. Platelet&[ndash]specific C5aR1 deletion reduced infarct size, fibrosis, and adverse remodeling while enhancing neovascularization and preserving cardiac function. Mechanistically, cell&[ndash]specific C5aR1 deletion markedly reduced myocardial platelet&[ndash]neutrophil accumulation and neutrophil extracellular trap (NET) formation, while circulating platelet&[ndash]neutrophil complexes were increased. Ex vivo, C5a&[ndash]stimulated platelets robustly induced NET release from neutrophils in a platelet C5aR1&[ndash] and CXCL4&[ndash]dependent manner, whereas platelets lacking C5aR1 failed to trigger NET formation. Pharmacological C5aR1 inhibition with PMX205 phenocopied the genetic platelet&[ndash]specific deletion, resulting in comparable cardioprotection. Together, these findings identify platelet C5aR1 as a druggable target of platelet&[ndash]neutrophil&[ndash]NET signaling that exacerbates myocardial injury and limits reparative healing after MI, highlighting platelet C5aR1 as a potential therapeutic approach to restrain thromboinflammation.

immunology↗

bioRxiv2021

A broadly neutralizing biparatopic Nanobody protects mice from lethal challenge with SARS-CoV-2 variants of concern

The ongoing COVID-19 pandemic and the frequent emergence of new SARS-CoV-2 variants of concern (VOCs), requires continued development of fast and effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nb) specific for the receptor-binding domain (RBD) of SARS-CoV-2, which are now being used as biparatopic Nbs (bipNbs) to investigate their potential as future drug candidates. Following detailed in vitro characterization, we chose NM1267 as the most promising candidate showing high affinity binding to several recently described SARS-CoV-2 VOCs and strong neutralizing capacity against a patient isolate of B.1.351 (Beta). To assess if bipNb NM1267 confers protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice were treated by intranasal route before infection with a lethal dose of SARS-CoV-2. NM1267-treated mice showed significantly reduced disease progression, increased survival rates and secreted less infectious virus via their nostrils. Histopathological analyses and in situ hybridization further revealed a drastically reduced viral load and inflammatory response in lungs of NM1267-treated mice. These data suggest, that bipNb NM1267 is a broadly active and easily applicable drug candidate against a variety of emerging SARS-CoV-2 VOCs.

biochemistry↗

bioRxiv2021

TPST-dependent and -independent regulation of root development and signaling by PSK LRR receptor kinases in Arabidopsis

Tyrosine-sulfated peptides are key regulators of plant growth and development. The disulfated pentapeptide phytosulfokine (PSK) mediates growth via leucine-rich repeat receptor-like kinases, PSKR1 and PSKR2. PSKRs are part of a response module at the plasma membrane that mediates short-term growth responses, but downstream signaling of transcriptional regulation remains unexplored. In Arabidopsis, tyrosine sulfation is catalyzed by a single-copy gene (TPST). We performed a microarray-based transcriptome analysis in the tpst-1 mutant background that lacks sulfated peptides to identify PSK-regulated genes and genes that are regulated by other sulfated peptides. Of the 160 PSK-regulated genes, several had functions in root growth and development in agreement with shorter roots and a higher lateral root density in tpst-1. Further, tpst-1 roots developed higher numbers of root hairs and PSK induced expression of WEREWOLF (WER), its paralog MYB DOMAIN PROTEIN 23 (MYB23) and At1g66800 that maintain non-hair cell fate. The tpst-1 pskr1-3 pskr2-1 mutant showed even shorter roots, and higher lateral root and root hair density than tpst-1 revealing unexpected synergistic effects of ligand and PSK receptor deficiencies. While residual activities may exist, overexpression of PSKR1 in the tpst-1 background induced root growth suggesting that PSKR1 may be active in the absence of sulfated ligands. HighlightPhytosulfokine (PSK) receptor signaling promotes root elongation, determines lateral root density and maintains non-hair cell fate partially independent of TPST responsible for the activating sulfation of PSK.

plant biology↗

bioRxiv2020

PSK signaling controls ABA homeostasis and promotes shoot growth under mannitol stress

Water deficit impairs growth and survival of plants. Many water stress responses are under control of abscisic acid (ABA) but little is known about growth control under osmotic stress. Based on the previously described growth-promoting activity of the peptide hormone phytosulfokine (PSK), we hypothesized that it may contribute to growth regulation under water stress conditions. To test this hypothesis, we analyzed the Arabidopsis thaliana PSK receptor (PSKR) null mutant pskr1-3 pskr2-1 under mannitol and drought stress. In particular under mild water stress, fresht weight and photosynthetic efficiency were more reduced in pskr1-3 pskr2-1 than in wild type. Hydroponic and grafting experiments showed that PSKR signaling was not required for long-distance signaling from mannitol-stressed roots to shoot but rather for cell growth promotion in the shoot. Unlike wild type, pskr1-3 pskr2-1 shoots did not accumulate ABA in response to mannitol, showed misregulation of ABA synthesis genes and elevated expression of ABI1 and ABI2, repressors of ABA signaling whereas application of ABA partially reversed shoot growth inhibition by mannitol in pskr1-3 pskr2-1. In turn, mannitol and ABA induced expression of PSK3 and PSKR1, and ABA promoted expression of PSK2 and PSK4 revealing feedback regulatory loops between PSKR and osmotic stress signaling. HighlightPhytosulfokine receptor signaling regulates ABA synthesis and signaling genes and promotes ABA accumulation in the shoot of water-stressed plants and maintains leaf growth and photosynthetic efficiency which ensures plant health.

plant biology↗

bioRxiv2020

Precursor processing by SBT3.8 and phytosulfokine signaling contribute to drought stress tolerance in Arabidopsis

Increasing drought stress poses a severe threat to agricultural productivity. Plants, however, evolved numerous mechanisms to cope with such environmental stress. Here we report that the stress-induced production of a peptide signal contributes to stress tolerance. The expression of phytosulfokine (PSK) peptide precursor genes, and transcripts of three subtilisin-like serine proteases, SBT1.4, SBT3.7 and SBT3.8 were found to be up-regulated in response to osmotic stress. Stress symptoms were enhanced in sbt3.8 loss-of-function mutants and could be alleviated by PSK treatment. Osmotic stress tolerance was improved in plants overexpression the precursor of PSK1 (proPSK1) or SBT3.8 resulting in higher fresh weight and improved lateral root development in the transgenic compared to wild-type plants. We further showed that SBT3.8 is involved in the biogenesis of the bioactive PSK peptide. ProPSK1 was cleaved by SBT3.8 at the C-terminus of the PSK pentapeptide. Processing by SBT3.8 depended on the aspartic acid residue adjacent to the cleavage site. ProPSK1 processing was impaired in the sbt3.8 mutant. The data suggest that increased expression in response to osmotic stress followed by the post-translational processing of proPSK1 by SBT3.8 leads to the production of PSK as a peptide signal for stress mitigation. HighlightThe expression of phytosulfokine precursor genes and processing by the subtilase SBT3.8 are upregulated in response to osmotic stress for improved drought tolerance in Arabidopsis.

plant biology↗

bioRxiv2018

The proto CpG island methylator phenotype of sessile serrated adenoma/polyps

Sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the {small tilde}20% of colon cancers with the CpG island methylator phenotype (CIMP), but their molecular features are poorly understood. We used high-throughput analysis of DNA methylation and gene expression to investigate the epigenetic phenotype of SSA/Ps. Fresh-tissue samples of 17 SSA/Ps and (for comparison purposes) 15 conventional adenomas (cADNs)--each with a matched sample of normal mucosa-- were prospectively collected during colonoscopy (total no. samples analyzed: 64). DNA and RNA were extracted from each sample. DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at {small tilde}2.7 million CpG sites located predominantly in gene regulatory regions and spanning 80.5Mb ({small tilde}2.5% of the genome); RNA was sequenced to define the samples transcriptomes. An independent series of 61 archival lesions was used for targeted verification of DNA methylation findings. Compared with normal mucosa samples, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions (3 SSA/P-specific and 3 common) demonstrated the high potential of DNA methylation markers for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression (n=618 genes vs 349 that were downregulated); downregulation was more common in cADNs (n=712 vs 516 upregulated genes). The epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue-based and noninvasive biomarkers that can add precision to the clinical management of the two most frequent colon-cancer precursors.

cancer biology↗

bioRxiv2018

A stress recovery signaling network for enhanced flooding tolerance in Arabidopsis thaliana

Abiotic stresses in plants are often transient and the recovery phase following stress removal is critical. Flooding, a major abiotic stress that negatively impacts plant biodiversity and agriculture, is a sequential stress where tolerance is strongly dependent on viability underwater and during the postflooding period. Here we show that in Arabidopsis thaliana accessions (Bay-0 and Lp2-6), different rates of submergence recovery correlate with submergence tolerance and fecundity. A genome-wide assessment of ribosome-associated transcripts in Bay-0 and Lp2-6 revealed a signaling network regulating recovery processes. Differential recovery between the accessions was related to the activity of three genes: RESPIRATORY BURST OXIDASE HOMOLOG (RBOHD), SENESCENCE-ASSOCIATED GENE113 (SAG113) and ORESARA1 (ORE1/NAC6) which function in a regulatory network involving a reactive oxygen species (ROS) burst upon de-submergence and the hormones abscisic acid and ethylene. This regulatory module controls ROS homeostasis, stomatal aperture and chlorophyll degradation during submergence recovery. This work uncovers a signaling network that regulates recovery processes following flooding to hasten the return to pre-stress homeostasis.\n\nSignificance statementFlooding due to extreme weather events can be highly detrimental to plant development and yield. Speedy recovery following stress removal is an important determinant of tolerance, yet mechanisms regulating this remain largely uncharacterized. We identified a regulatory network in Arabidopsis thaliana that controls water loss and senescence to influence recovery from prolonged submergence. Targeted control of the molecular mechanisms facilitating stress recovery identified here can potentially improve performance of crops in flood-prone areas.

plant biology↗