Biology subjects

Rathkolb, B.

Publications and source records attributed to Rathkolb, B..

7 recordsLinked to original sources

bioRxiv2024

Characterization of liver-pancreas crosstalk following beta-cell loss reveals a role for the molybdenum cofactor in beta-cell regeneration

Regeneration of insulin-producing {beta}-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of {beta}-cells. Here, we aimed to characterize how hepatocytes can contribute to {beta}-cell regeneration in a zebrafish model of {beta}-cell ablation. Using lineage-tracing, we show that hepatocytes do not directly convert into {beta}-cells even under extreme {beta}-cell ablation conditions. A transcriptomics analysis of isolated hepatocytes following {beta}-cell ablation displayed altered lipid- and glucose-related processes. Based on the transcriptomics, we performed a genetic screen that uncovers a potential role for the molybdenum cofactor (Moco) biosynthetic pathway in {beta}-cell regeneration and glucose metabolism in zebrafish. Consistently, Mocs2 haploinsufficiency in mice indicated dysregulated glucose metabolism and liver function. Together, our study sheds light on the liver-pancreas crosstalk and suggests that the molybdenum cofactor biosynthesis pathway should be further studied in relation to glucose metabolism and diabetes.

developmental biology↗

bioRxiv2024

eATP/P2X7R axis drives nanoparticle induced neutrophil recruitment in the pulmonary microcirculation

Exposure to nanoparticles (NPs) is frequently associated with adverse cardiovascular effects. In contrast, NPs in nanomedicine hold great promise for precise lung-specific drug delivery, especially considering the extensive pulmonary capillary network that facilitates interactions with bloodstream-suspended particles. Therefore, exact knowledge about interactions and effects of engineered NPs with the pulmonary microcirculation are instrumental for future application of this technology in patients. To unravel the real-time dynamics of intravenously delivered NPs and their effects in the pulmonary microvasculature, we employed intravital microscopy of the mouse lung. PEG amine-modified quantum dots (aQDs) with a low potential for biomolecule and cell interactions and carboxyl-modified quantum dots (cQDs) with a high interaction potential were used, representing two different NP subtypes. Only aQDs triggered rapid neutrophil recruitment in microvessels and their subsequent recruitment to the alveolar space. Application of specific inhibitors revealed that the aQDs induced neutrophil recruitment was linked to cellular degranulation, TNF-, and DAMP release into the circulation, particularly extracellular ATP (eATP). Stimulation of the ATP-gated P2X7R induced the expression of E-selectin on microvascular endothelium with the subsequent E-selectin depended neutrophilic immune response. Leukocyte integrins (LFA-1 and MAC-1) mediated adhesion and reduction in neutrophil crawling velocity on the vascular surface. In summary, this study unravels the complex cascade of neutrophil recruitment during NP-induced sterile inflammation. Thereby we demonstrate novel adverse effects for NPs in the pulmonary microcirculation and provide critical insights for optimizing NP-based drug delivery and therapeutic intervention strategies, to ensure their efficacy and safety in clinical applications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/584398v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@d10acborg.highwire.dtl.DTLVardef@1bbfe7org.highwire.dtl.DTLVardef@1d3e415org.highwire.dtl.DTLVardef@2328de_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Comparative phenotyping of mice reveals canonical and noncanonical physiological functions of TRα and TRβ

Thyroid hormone (TH) effects are mediated through TH receptors (TRs) TR1, TR{beta}1, and TR{beta}2. The TRs bind to thyroid hormone responsive elements on the DNA and regulate expression of TH target genes as ligand dependent transcription factors (canonical signaling). In addition, the TRs and {beta} mediate activation of signaling pathways, e.g. the PI3K/AKT and MAPK/ERK pathways (noncanonical signaling). Whether such DNA-binding independent TR action contributes to the spectrum of physiological TH effects is largely unknown. The aim of this study was to attribute physiological effects to the two TR isoforms and {beta} and their canonical and noncanonical signaling. We conducted multi-parameter phenotyping in male and female TR knockout mice (TRKO, TR{beta}KO), mice with disrupted canonical signaling due to a mutation in the TR DNA-binding domain (TRGS, TR{beta}GS) and their respective wild-type littermates. Perturbations in senses, especially hearing (mainly TR{beta} with a lesser impact of TR), visual acuity and retinal thickness (TR and TR{beta}), in muscle metabolism (TR) and in heart rate (TR) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little to no phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization or increased anxiety related behavior were only observed in TRKO, but not TRGS mice. Noncanonical TR action increased the efficiency of energy utilization and prevented hyperphagia observed in TRKO mice. In summary, by examining the phenotypes of TR and TR{beta} knockout models alongside their DNA-binding-deficient GS mutants and wildtype counterparts, we could establish that the independent noncanonical actions of TR and TR{beta} play a crucial role in modulating sensory, behavioral, and metabolic functions. This comparison underscores the significance of the TRs in orchestrating a spectrum of physiological processes beyond their traditional genomic pathways.

physiology↗

bioRxiv2022

New C3H KitN824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance

Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT-mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT-variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H KitN824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous KIT-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.

cancer biology↗

bioRxiv2022

Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice

Current concepts regarding the biology of aging are based on studies aimed at identifying factors regulating natural lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific sets of pathologies, rather than by general physiological decline. Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/6J mice. For each phenotype, we established lifetime profiles to determine when age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions, PAAIs; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans. We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging. HighlightsO_LIPhenotyping at scale defines lifetime trajectories of age-dependent changes in C57BL/6J mice C_LIO_LICentral genetic and environmental lifespan regulators (putative anti-aging interventions; PAAIs) influence age-sensitive phenotypes (ASPs) often long before the appearance of age-dependent changes in these ASPs C_LIO_LICorresponding genetic variants in humans also have age-independent effects C_LIO_LIMany PAAI effects shift the baseline of ASPs rather than slowing their rate of change C_LI

physiology↗

bioRxiv2021

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these indicate hypometabolism, energetic inflexibility and increased stores at the expense of active tissue as energy shortage consequences.

physiology↗

bioRxiv2020

Titan Mice are Unique Short-Lived Mammalian Model of Metabolic Syndrome and Aging

Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The outbred mouse line Titan (DU6) results from the worlds longest selection experiment for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study deeper characterized the geno- and phenotypes of this outbred mouse line and tested its suitability as an interventional obesity model. In contrast to previous findings, our data suggests that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice show modifications in the liver transcriptome, proteome and epigenome that are linked to metabolic (dys)regulations. However, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research.

biochemistry↗